GastrointestinalPhysiology

EIGHTH EDITION

Leonard R. Johnson,PhDThomas A. Gerwin Professor of Physiology,University of Tennessee Health Sciences Center,Memphis, Tennessee

Table of Contents

Instructions for online access

Cover image

Title page

Series page

Copyright

Preface

Chapter 1: Regulation: Peptides of theGastrointestinal Tract

General Characteristics

Discovery

Chemistry

Distribution And Release

Actions And Interactions

Candidate Hormones

Neurocrines

Paracrines

Summary

Chapter 2: Regulation: Nerves and SmoothMuscle

Anatomy Of The Autonomic Nervous System

Neurohumoral Regulation Of GastrointestinalFunction

Anatomy Of The Smooth Muscle Cell

Smooth Muscle Contraction

Summary

Chapter 3: Swallowing

Chewing

Pharyngeal Phase

Esophageal Peristalsis

Receptive Relaxation Of The Stomach

Summary

Chapter 4: Gastric Emptying

Anatomic Considerations

Contractions Of The Orad Region Of The Stom-ach

Contractions Of The Caudad Region Of TheStomach

Contractions Of The Gastroduodenal Junction

Contractions Of The Proximal Duodenum

Regulation Of Gastric Emptying

Summary

Chapter 5: Motility of the Small Intestine

Anatomic Considerations

Types Of Contractions

Patterns Of Contractions

Vomiting

Summary

Chapter 6: Motility of the Large Intestine

Anatomic Considerations

Contractions Of The Cecum And Ascending Co-lon

Contractions Of The Descending And SigmoidColon

Motility Of The Rectum And Anal Canal

Control Of Motility

Summary

Chapter 7: Salivary Secretion

Functions Of Saliva

Anatomy And Innervation Of The SalivaryGlands

Composition Of Saliva

Regulation Of Salivary Secretion

Summary

Chapter 8: Gastric Secretion

Functional Anatomy

Secretion Of Acid

Origin Of The Electrical Potential Difference

Electrolytes Of Gastric Juice

Stimulants Of Acid Secretion

Stimulation Of Acid Secretion

Inhibition Of Acid Secretion

Pepsin

Mucus

Intrinsic Factor

Growth Of The Mucosa

Summary

Chapter 9: Pancreatic Secretion

Functional Anatomy

Mechanisms Of Fluid And Electrolyte Secretion

Mechanisms Of Enzyme Secretion

Regulation Of Secretion

Cellular Basis For Potentiation

Response To A Meal

Summary

Chapter 10: Bile Secretion and GallbladderFunction

Overview Of The Biliary System

Constituents Of Bile

Bile Secretion

Gallbladder Function

Expulsion Of Bile

Summary

Chapter 11: Digestion and Absorption ofNutrients

Structural-Functional Associations

Digestion

Absorption

Adaptation Of Digestive And Absorptive Pro-cesses

Carbohydrate Assimilation

Protein Assimilation

Lipid Assimilation

Vitamins

Summary

Chapter 12: Fluid and Electrolyte Absorp-tion

Bidirectional Fluid Flux

Ionic Content Of Luminal Fluid

Transport Routes And Processes

Mechanism For Water Absorption And Secretion

Intestinal Secretion

Calcium Absorption

Iron Absorption

Summary

Chapter 13: Regulation of Food Intake

Appetite Control

The Nervous System

The Endocrine System

The Gastrointestinal System

Summary

Appendix

Index

Series page

Look for these other volumes in the MosbyPhysiology Monograph Series titles:

Blaustein et al: CELLULAR PHYSIOLOGYAND NEUROPHYSIOLOGY

Cloutier: RESPIRATORY PHYSIOLOGYHudnall: HEMATOLOGYWhite & Porterfield: ENDOCRINE AND

REPRODUCTIVE PHYSIOLOGYKoeppen & Stanton: RENAL PHYSIOLOGYPappano & Weir: CARDIOVASCULAR

PHYSIOLOGY

Copyright

1600 John F. Kennedy Blvd.Ste 1800Philadelphia, PA 19103-2899GASTROINTESTINALPHYSIOLOGY ISBN:978-0-323-10085-4

Copyright © 2014, 2007 by Mosby, an im-print of Elsevier Inc.

All rights reserved. No part of this publica-tion may be reproduced or transmitted inany form or by any means, electronic or

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Notices

Knowledge and best practice inthis field are constantly changing.As new research and experiencebroaden our understanding,changes in research methods,

professional practices, or medicaltreatment may become necessary.Practitioners and researchersmust always rely on their ownexperience and knowledge inevaluating and using any inform-ation, methods, compounds, orexperiments described herein. Inusing such information or meth-ods they should be mindful oftheir own safety and the safety ofothers, including parties forwhom they have a professionalresponsibility. With respect toany drug or pharmaceuticalproducts identified, readers areadvised to check the most currentinformation provided (i) on pro-cedures featured or (ii) by themanufacturer of each product tobe administered, to verify the re-commended dose or formula, the

method and duration of adminis-tration, and contraindications. Itis the responsibility of practition-ers, relying on their own experi-ence and knowledge of their pa-tients, to make diagnoses, to de-termine dosages and the besttreatment for each individual pa-tient, and to take all appropriatesafety precautions. To the fullestextent of the law, neither thePublisher nor the authors, con-tributors, or editors, assume anyliability for any injury and/ordamage to persons or property asa matter of products liability,negligence or otherwise, or fromany use or operation of anymethods, products, instructions,or ideas contained in the materialherein.

Library of Congress Cataloging-in-Publica-tion DataJohnson, Leonard R., 1942- author.Gastrointestinal physiology / Leonard R.Johnson. —Eighth edition.

p. ; cm. —(Mosby physiology monographseries)Preceded by Gastrointestinal physiology /edited by Leonard R. Johnson. 7th ed. c2007.Includes bibliographical references and in-dex.ISBN 978-0-323-10085-4 (pbk.)I. Title. II. Series: Mosby physiology mono-graph series.[DNLM: 1. Digestive System PhysiologicalPhenomena. WI 102]QP145612.3—dc23 2013016769Senior Content Strategist: Elyse O’GradySenior Content Development Specialist: Mary-beth ThielContent Development Specialist: Maria Hol-man

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Preface

The first edition of Gastrointestinal Physiologyappeared in 1977. It developed as a result ofthe authors’ teaching experiences and theneed for a book on gastrointestinalphysiology written and designed for medicalstudents and beginning graduate students.This eighth edition is directed to the sameaudience. As with any new edition, I believethat it is significantly better than the previousone. All chapters contain considerableamounts of new material and have beenbrought up-to-date with current information,without introducing undue amounts of con-troversy to confuse students. New figures

have been added, others updated, and somechapters significantly rewritten.

Major changes in this edition are the ad-dition of a list of “Objectives” at the begin-ning of chapters and “Clinical Applications”boxes within chapters. Hopefully the learn-ing objectives will provide a guide to theimportant concepts and be an aid to under-standing them. The material presented asclinical applications is meant to emphasizethe significance of some of the basic science,provide some perspective, and increase stu-dent interest.

I am grateful to my own students forpointing out ways to improve the book.Numerous colleagues in other medicalschools and professional institutions haveadded their suggestions and criticisms aswell. I am thankful for their interest andhelp, and I hope that anyone having criti-cisms of this edition or suggestions for im-proving future editions will transmit them tome.

This is the first edition appearing undersole authorship. In all previous editions, themotility chapters were written by Dr. Nor-man W. Weisbrodt, who has since retired. Iam grateful to him for allowing me to use hismaterial as I saw fit.

I would like to thank H.J. Ehrlein and Mi-chael Schemann for generously allowing usto link the videos referenced in Chapters 4and 5, which appear on the website of theTechnische Universität München ( ht-tp://www.wzw.tum.de/humanbiology/data/motility/34/?alt=english). The videofluoro-scopy on gastrointestinal motility of dogs,pigs, and sheep was performed during thescientific studies of H.J. Ehrlein and his col-leagues over a period of 25 years. This videoproject was supported by an educationalgrant from Janssen Research Foundation.

Finally, I thank Ms. Marybeth Thiel of El-sevier for suggestions and for helping withthe communications and organizational

work that are a necessary part of such a pro-ject.

Leonard R. Johnson

Regulation

Peptides of theGastrointestinal Tract

Object ives

Describe the four major functions of thegastrointestinal (GI) tract.Understand the differences between andsignificance of endocrine, paracrine, andneurocrine agents.

Identify the major GI hormones, their func-tions, sites of release, and stimuli for re-lease.Identify the important neurocrines andtheir functions in the GI tract.Identify the important paracrines and theirfunctions in the GI tract.Understand the causes and resultingphysiology of gastrinoma (Zollinger-Ellisonsyndrome) and pancreatic cholera (Wern-er Morrison syndrome).

The functions of the gastrointestinal (GI)tract are regulated by peptides, derivativesof amino acids, and a variety of mediatorsreleased from nerves. All GI hormones arepeptides, but it is important to realize thatnot all peptides found in digestive tract mu-cosa are hormones. The GI tract peptides canbe divided into endocrines, paracrines, and

neurocrines, depending on the method bywhich the peptide is delivered to its targetsite.

Endocrines, or hormones, are released in-to the general circulation and reach all tis-sues (unless these substances are excludedfrom the brain by the blood-brain barrier).Specificity is a property of the target tissue it-self. Specific receptors, which recognize andbind the hormone, are present on its targettissues and absent from others. There are fiveestablished GI hormones; in addition, someGI peptides are released from endocrine cellsinto the blood but have no known physiolo-gic function. Conversely, several peptideshave been isolated from mucosal tissue andhave potent GI effects, but no mechanismfor their physiologic release has been found.Members of these latter two groups are clas-sified as candidate hormones.

Paracrines are released from endocrinecells and diffuse through the extracellularspace to their target tissues. Their effects are

limited by the short distances necessary fordiffusion. Nevertheless, these agents can af-fect large areas of the digestive tract by vir-tue of the scattered and abundant distribu-tions of the cells containing them. A parac-rine agent can also act on endocrine cells.Thus a paracrine may release or inhibit therelease of an endocrine substance, therebyultimately regulating a process remote fromits origin. Histamine, a derivative of theamino acid histidine, is an important regu-latory agent that acts as a paracrine.

Some GI peptides are located in nervesand may act as neurocrines or neurotrans-mitters. A neurocrine is released near its tar-get tissue and needs only to diffuse across ashort synaptic gap. Neurocrines conceivablymay stimulate or inhibit the release of endo-crines or paracrines. Acetylcholine (ACh),although not a peptide, is an importantneuroregulator in the GI tract. One of its ac-tions is to stimulate acid secretion from thegastric parietal cells.

General CharacteristicsThe GI tract is the largest endocrine organ inthe body, and its hormones were the first tobe discovered. The word hormone was coinedby W. B. Hardy and used by Starling in 1905to describe secretin and gastrin and to conveythe concept of bloodborne chemical messen-gers. The GI hormones are released from themucosa of the stomach and small intestineby nervous activity, distention, and chemicalstimulation coincident with the intake offood. Released into the portal circulation, theGI hormones pass through the liver to theheart and back to the digestive system to reg-ulate its movements, secretions, and growth.These hormones also regulate the growth ofthe mucosa of the stomach and small andlarge intestines, as well as the growth of theexocrine pancreas.

The GI peptides have many different typesof actions. Their effects on water, electrolyte,

and enzyme secretion are well known, butthey also influence motility, growth, and re-lease of other hormones, as well as intestinalabsorption. Many of these actions overlap;two or more GI peptides may affect the sameprocess in the same direction, or they mayinhibit each other. Many of the demon-strated actions of these peptides are phar-macologic and do not occur under normalcircumstances. This chapter is concernedprimarily with the physiologic effects of theGI peptides.

The actions of the GI peptides also mayvary in both degree and direction amongspecies. The actions discussed in the re-mainder of this chapter are those occurringin humans.

DiscoveryFour steps are required to establish the ex-istence of a GI hormone. First, a physiologicevent such as a meal must be demonstrated toprovide the stimulus to one part of the digest-ive tract that subsequently alters the activityin another part. Second, the effect must per-sist after all nervous connections between thetwo parts of the GI tract have been severed.Third, from the site of application of the stim-ulus a substance must be isolated that, wheninjected into the blood, mimics the effect ofthe stimulus. Fourth, the substance must beidentified chemically, and its structure mustbe confirmed by synthesis.

Five GI peptides have achieved full statusas hormones. They are secretin, gastrin,cholecystokinin (CCK), gastric inhibitorypeptide (GIP), and motilin. There is also anextensive list of “candidate” hormones whosesignificance has not been established. This list

includes several chemically defined peptidesthat have significant actions in physiologyor pathology but whose hormonal status hasnot been proved. These are pancreatic poly-peptide, neurotensin, and substance P. In ad-dition, two known hormones, glucagon andsomatostatin, have been identified in GI tractmucosa; their possible function as GI hor-mones is currently being investigated. Someof these peptides function physiologically asparacrines or neurocrines. Another GI pep-tide, Ghrelin, is released from the body ofthe stomach and functions as a hormone toregulate food intake. This topic is covered inChapter 13.

Secretin, the first hormone, was dis-covered in 1902 by Bayliss and Starling andwas described as a substance, released fromthe duodenal mucosa by hydrochloric acid,that stimulated pancreatic bicarbonate andfluid secretion. Jorpes and Mutt isolated itand identified its amino acid sequence in

1966. It was synthesized by Bodanszky andcoworkers later the same year.

Edkins discovered gastrin in 1905, statingto the Royal Society that “in the process ofthe absorption of digested food in the stom-ach a substance may be separated from thecells of the mucous membrane which,passing into the blood or lymph, later stim-ulates the secretory cells of the stomach tofunctional activity.” For 43 years investig-ators were preoccupied by the controversyover the existence of gastrin. The debate in-tensified when Popielski demonstrated thathistamine, a ubiquitous substance present inlarge quantities throughout the body (in-cluding the gastric mucosa), was a powerfulgastric secretagogue. In 1938 Komarovdemonstrated that gastrin was a polypeptideand was different from histamine. By 1964Gregory and his colleagues had extractedand isolated hog gastrin; Kenner and hisgroup synthesized it the same year. After 60

years all of the criteria for establishing theexistence of a GI hormone had been satisfied.

In 1928 Ivy and Oldberg described ahumoral mechanism for the stimulation ofgallbladder contraction initiated by the pres-ence of fat in the intestine. The hormone wasnamed cholecystokinin after its primary ac-tion. The only controversy involving CCKwas a mild one over nomenclature. In 1943Harper and Raper described a hormone re-leased from the small intestine that stimu-lated pancreatic enzyme secretion and ac-cordingly named it pancreozymin. As Jorpesand Mutt carried out the purification of thesetwo substances in 1968, it became obviousthat both properties resided in the same pep-tide. For the sake of convenience and be-cause it was the first action described, thishormone is called CCK.

In 1969 Brown and his coworkers de-scribed the purification of a powerful entero-gastrone from intestinal mucosa. Enterogast-rone literally means a substance from the in-

testine (entero-) that inhibits (-one) the stom-ach (gastr-). By 1971 this peptide had beenpurified, isolated, sequenced, and namedgastric inhibitory peptide for its ability to in-hibit gastric secretion. Released from the in-testinal mucosa by fat and glucose, GIP alsostimulates insulin release. Following proofthat the release of insulin was a physiologicaction of the peptide, GIP became the fourthGI hormone. The insulinotropic effect of GIPrequires elevated amounts of serum glucose.For this reason, and because it is doubtfulwhether the inhibitory effects of the peptideon the stomach are physiologic, it has beensuggested that its name be changed toglucose-dependent insulinotropic peptide.In either case it is still referred to as GIP.

Brown and his coworkers also describedthe purification of motilin in the early 1970s.Motilin is a linear 22–amino acid peptidepurified from the upper small intestine. Dur-ing fasting it is released cyclically and stim-ulates upper GI motility. Its release is under

neural control and accounts for the interdi-gestive migrating myoelectric complex.

ChemistryThe GI hormones and some related peptidescan be divided into two structurally homolog-ous families. The first consists of gastrin ( Fig.1-1) and CCK ( Fig. 1-2). The five carboxyl-ter-minal (C-terminal) amino acids are identicalin these two hormones. All the biologic activ-ity of gastrin can be reproduced by the four C-terminal amino acids. This tetrapeptide, then,is the minimum fragment of gastrin neededfor strong activity and is about one sixth asactive as the whole 17–amino acid molecule.The sixth amino acid from the C-terminus ofgastrin is tyrosine, which may or may not besulfated. When sulfated, the hormone iscalled gastrin II. Both forms occur with equalfrequency in nature. The amino-terminus (N-terminus) of gastrin is pyroglutamyl, and theC-terminus is phenylalamide (see Fig. 1-1).The NH2 group following Phe does not signi-fy that this is the N-terminus; rather, it indic-

ates that this C-terminal amino acid is amid-ated. These alterations in structure protectthe molecules from aminopeptidases andcarboxypeptidases and allow most of themto pass through the liver without being inac-tivated.

FIGURE 1-1 Structure of human little gast-rin (G 17).

FIGURE 1-2 Structure of porcinecholecystokinin (CCK).

Gastrin is first synthesized as a large, bio-logically inactive precursor called progast-rin. A glycine-extended (G-Gly) form ofgastrin is then formed by endoproteolyticprocessing within the G cells. G-Gly is thesubstrate for an amidation reaction that res-

ults in the formation of the mature, amidatedgastrin. The C-terminal amide moiety is re-quired for full biologic activity mediated bygastrin/CCK-2 receptors. Receptors for CCKand gastrin were originally called the CCK-A and CCK-B receptors, respectively; the no-menclature has been changed to CCK-1 andCCK-2. G-Gly does not stimulate the gastrin/CCK-2 receptor but instead activates its ownreceptor, thus leading to the activation of Junkinase and trophic effects.

CCK, which has 33 amino acids, containsa sulfated tyrosyl residue in position 7 fromthe C-terminus (see Fig. 1-2). CCK can activ-ate gastrin receptors (e.g., those for acid se-cretion, also called CCK-2 receptors); gast-rin can activate CCK receptors (e.g., those forgallbladder contraction, also called CCK-1receptors). Each hormone, however, is morepotent at its own receptor than at those ofits homologue. CCK is always sulfated innature, and desulfation produces a peptidewith the gastrin pattern of activity. The min-

imally active fragment for the CCK patternof activity is therefore the C-terminal hep-tapeptide.

In summary, peptides belonging to thegastrin/CCK family having a tyrosyl residuein position 6 from the C-terminus or an un-sulfated one in position 7 possess the gastrinpattern of activity and act on CCK-2 recept-ors—strong stimulation of gastric acid secre-tion and weak contraction of the gallbladder.Peptides with a sulfated tyrosyl residue inposition 7 act on CCK-1 receptors, havecholecystokinetic potency, and are weakstimulators of gastric acid secretion. Obvi-ously the tetrapeptide itself and all frag-ments less than seven amino acids long pos-sess gastrin-like activity.

The second group of peptides is homolog-ous to secretin and includes vasoactive in-testinal peptide (VIP), GIP, and glucagon,in addition to secretin ( Fig. 1-3). Secretinhas 27 amino acids, all of which are requiredfor substantial activity. Pancreatic glucagon

has 29 amino acids, 14 of which are identicalto those of secretin. Glucagon-like immun-oreactivity has been isolated from the smallintestine, but the physiologic significance ofthis enteroglucagon has not been estab-lished. Glucagon has no active fragment,and, like secretin, the whole molecule is re-quired before any activity is observed. Evid-ence indicates that secretin exists as a helix;thus the entire amino acid sequence may benecessary to form a tertiary structure withbiologic activity.

FIGURE 1-3 Structures of the secretinfamily of peptides. GIP, gastric inhibitorypeptide; VIP, vasoactive intestinal peptide.

GIP and VIP each have nine amino acidsthat are identical to those of secretin. Eachhas many of the same actions as those ofsecretin and glucagon. This group of pep-tides is discussed in greater detail later in thechapter.

Most peptide hormones are heterogen-eous and occur in two or more molecularforms. Gastrin, secretin, and CCK all havebeen shown to exist in more than one form.

Gastrin was originally isolated from hog an-tral mucosa as a heptadecapeptide (see Fig.1-1), which is now referred to as little gastrin(G 17). It accounts for 90% of antral gastrin.Yalow and Berson demonstrated heterogen-eity by showing that the major component ofgastrin immunoactivity in the serum was alarger molecule that they called big gastrin.On isolation, big gastrin was found to con-tain 34 amino acids; hence it is called G 34.Trypsin splits G 34 to yield G 17 plus a hept-adecapeptide different from G 17. Therefore,G 34 is not simply a dimer of G 17. An addi-tional gastrin molecule (G 14) has been isol-ated from tissue and contains the C-terminaltetradecapeptide of gastrin. Current eviden-ce indicates that most G 17 is produced frompro G 17 and most G 34 is derived from proG 34. Thus G 34 is not a necessary intermedi-ate in the production of G 17.

During the interdigestive (basal) state,most human serum gastrin is G 34. Unlikethose of other species, the duodenal mucosa

of humans contains significant amounts ofgastrin. This is primarily G 34 and is releasedin small amounts during the basal state.After a meal, a large quantity of antral gast-rin, primarily G 17, is released and providesmost of the stimulus for gastric acid secre-tion. Smaller amounts of G 34 are releasedfrom both the antral and the duodenal mu-cosa. G 17 and G 34 are equipotent, althoughthe half-life of G 34 is 38 minutes and that ofG 17 is approximately 7 minutes. The plasmaconcentration of gastrin in fasting humansis 10 to 30 pmol/L, and it doubles or triplesduring the response to a normal mixed meal.

Distribution and ReleaseThe GI hormones are located in endocrinecells scattered throughout the GI mucosafrom the stomach through the colon. The cellscontaining individual hormones are notclumped together but are dispersed amongthe epithelial cells. The nature of this distribu-tion makes it virtually impossible to removethe source of one of the GI hormones sur-gically and examine the effect of its absencewithout compromising the digestive functionof the animal.

The endocrine cells of the gut are membersof a widely distributed system termed amineprecursor uptake decarboxylation (APUD)cells. These cells all are derived fromneuroendocrine-programmed cells originat-ing in the embryonic ectoblast.

The distributions of the individual GI hor-mones are shown in Figure 1-4. Gastrin ismost abundant in the antral and duodenal

mucosa. Most of its release under physiolo-gic conditions is from the antrum. Secretin,CCK, GIP, and motilin are found in the duo-denum and jejunum.

FIGURE 1-4 Distribution of thegastrointestinal hormones. Shaded areas in-dicate where the most release occurs undernormal conditions. CCK, cholecystokinin;GIP, gastric inhibitory peptide.

Ultrastructurally, GI endocrine cells havehormone-containing granules concentratedat their bases, close to the capillaries. Thegranules discharge, thereby releasing their

hormones in response to events that areeither the direct or the indirect result of neur-al, physical, and chemical stimuli associatedwith eating a meal and the presence of thatmeal within the digestive tract. These endo-crine cells have microvilli on their apical bor-ders that presumably contain receptors forsampling the luminal contents.

Table 1-1 lists the stimuli that arephysiologically important releasers of the GIhormones. Gastrin and motilin are the onlyhormones shown to be released directly byneural stimulation. Protein in the form ofpeptides and single amino acids releasesboth gastrin and CCK. Fatty acids containingeight or more carbon atoms or theirmonoglycerides are the most potent stimulifor CCK release. Fat must be broken downinto an absorbable form before release ofCCK, thus providing evidence that the re-ceptors for release are triggered during theprocess of absorption.

TABLE 1-1Releasers of Gastrointestinal Hormones

CCK, cholecystokinin; GIP, gastric inhibitory peptide;I, inhibits release physiologically; S, physiologic stim-ulus for release; S-, of secondary importance; 0, noeffect.

Evidence indicates that intestinal releasingfactors secreted into the intestine of certainspecies, including humans, stimulate the re-lease of CCK. Pancreatic enzymes inactivatethese releasing factors. The ingestion andpresence of a meal in the intestine result intemporary binding of trypsin and other pro-

teases and allow the releasing factors to re-main active and stimulate CCK secretion.Thus this mechanism acts as a negative feed-back control on pancreatic enzyme secretion.

Carbohydrate, the remaining major food-stuff, does not alter the release of gastrin,secretin, or CCK to a significant extent butdoes stimulate GIP release. GIP also is re-leased by fat and protein. The strongest stim-ulus for secretin release is H+. Secretin is re-leased when the pH in the duodenum fallsbelow 4.5. Secretin also is released by fattyacids. This may be a significant mechanismfor secretin release because the concentrationof fatty acids in the lumen is often high. CCKcan also be released by acid, but except dur-ing hypersecretion of acid, the physiologicsignificance of this mechanism of release hasnot been established. The purely physicalstimulus of distention activates antral re-ceptors and causes gastrin release; for ex-ample, inflating a balloon in the antrum re-leases gastrin. During a meal the pressure

of ingested food initiates this response. Themagnitude of the response is not as great asoriginally believed, however, and the con-tribution of distention to the total amountof gastrin released in humans probably isminor. Gastrin also can be released by cal-cium, decaffeinated coffee, and wine. Purealcohol in the same concentration as that ofwine does not release gastrin but does stimu-late acid secretion. Motilin is released cyclic-ally (approximately every 90 minutes) dur-ing fasting. This release is prevented by at-ropine and ingestion of a mixed meal. Acidand fat in the duodenum, however, increasemotilin release.

In addition to releasing secretin, acid ex-erts an important negative feedback controlof gastrin release. Acidification of the antralmucosa below a pH of 3.5 inhibits gastrinrelease. Patients with atrophic gastritis, per-nicious anemia, or other conditions charac-terized by the chronic decrease of acid-se-creting cells and hyposecretion of acid may

have extremely high serum concentrations ofgastrin because of the absence of this inhibit-ory mechanism.

Hormones alter the release of GI peptidesin several instances. Both secretin and glu-cagon, for example, inhibit gastrin release.CCK has been shown to stimulate glucagonrelease, and four GI hormones (secretin,gastrin, CCK, and GIP) increase insulin se-cretion. Elevated serum calcium stimulatesboth gastrin and CCK release. It is doubtfulwhether any of these mechanisms, with theexception of release of insulin by GIP, play arole in normal GI physiology. Some mechan-isms, however, may become important whencirculating levels of hormones or calcium arealtered by disease.

Actions and InteractionsThe effects of pure GI hormones have beentested on almost every secretory, motor, andabsorptive function of the GI tract. Each pep-tide has some action on almost every targettested. Even though large doses of hormonesometimes are necessary to produce an effect,either stimulatory or inhibitory, these tests in-dicate that receptors for each hormone arepresent on most target tissues. The myriadactivities possessed by these peptides aresummarized in Table 1-2.

TABLE 1-2Actions of Gastrointestinal Hormones

CCK, cholecystokinin; GIP, gastric inhibitory peptide;

, bicarbonate; I, inhibits; S, stimulates;

0, no effect; blank spaces, not yet tested.

The important physiologic actions of theGI hormones are depicted in Table 1-3.Numerous guidelines have been proposedfor determining whether an action isphysiologic. The action should occur in re-sponse to endogenous hormone released bynormal stimuli (i.e., those present during ameal). In other words, an exogenous dose ofhormone should produce the effect in ques-tion without elevating serum hormone levelsabove those produced by a meal. An accept-able guideline for exogenous infusion is adose that produces 50% of the maximal re-sponse (D50) of the primary action of the hor-mone. The hormone should be administeredas a continuous intravenous infusion ratherthan as a single bolus because the a bolusproduces transient, unphysiologically highserum levels.

TABLE 1-3Important Actions of GastrointestinalHormones

CCK, cholecystokinin; GIP, gastric inhibitory peptide;

, bicarbonate; I, inhibits; S, stimulates.

The primary action of gastrin is the stim-ulation of gastric acid secretion. It does thisby causing the release of histamine (a potentacid secretagogue) from theenterochromaffin-like (ECL) cells of thestomach and by direct action on the parietalcells. Gastrin is the most important regulatorof gastric acid secretion. There is consider-able debate on the role of gastrin in regulat-ing the tone of the lower esophageal sphinc-ter, and the bulk of the evidence indicates nonormal role for gastrin in regulation.

One of the most important and more re-cently discovered actions of GI hormones istheir trophic activity. Gastrin stimulates syn-thesis of ribonucleic acid (RNA), protein,and deoxyribonucleic acid (DNA), as well asgrowth of the mucosa of the small intestine,colon, and oxyntic gland area of the stomach.If most endogenous gastrin is removed byantrectomy, these tissues atrophy. Exogen-ous gastrin prevents this atrophy. Patientswith tumors that constantly secrete gastrin

exhibit hyperplasia and hypertrophy of theacid-secreting portion of the stomach.Gastrin also stimulates the growth of ECLcells. Continued hypersecretion of gastrinresults in ECL cell hyperplasia, which maydevelop into carcinoid tumors. The trophiceffects of gastrin are restricted to GI tissuesand are counteracted by secretin. The trophicaction of gastrin is a direct effect that can bedemonstrated in tissue culture.

As mentioned previously, G-Gly also hastrophic effects. G-Gly is far less potent (byat least four orders of magnitude) than gast-rin in stimulating gastric acid secretion.However, G-Gly is stored in gut tissues, issecreted with gastrin from antral G cells, andreaches concentrations in plasma equal tothose of gastrin. Although antagonists of theCCK-B/gastrin receptor block the trophic ef-fects of gastrin, they have no effect on thegrowth-promoting actions of G-Gly. Addi-tional evidence suggests that the growth-re-lated receptors for G-Gly work in concert

with gastrin to regulate the functional devel-opment of the gut.

The primary effect of secretin is the stimu-lation of pancreatic fluid and bicarbonate se-cretion; one of the primary actions of CCKis the stimulation of pancreatic enzyme se-cretion. In addition, CCK has a physiologic-ally important interaction in potentiating theprimary effect of secretin. Thus CCK greatlyincreases the pancreatic bicarbonate re-sponse to low circulating levels of secretin.

Both CCK and secretin also stimulate thegrowth of the exocrine pancreas. CCK exertsa stronger effect than secretin, but the com-bination of the two hormones produces a po-tentiated response in rats that is truly re-markable. It is likely that the effects of thesetwo hormones on pancreatic growth are asimportant as their effects on pancreatic se-cretion.

In addition to its effects on the pancreas,secretin stimulates biliary secretion of fluidand bicarbonate. This action is shared by

CCK, but secretin is the most potentcholeretic of the GI hormones. In dogs, se-cretin is a potent inhibitor of gastrin-stimu-lated acid secretion. This action is probablynot physiologically important in humans.The ability of secretin to inhibit acid secre-tion may be important in some human dis-eases, however, and students should beaware of this action. Secretin has been nick-named “nature’s antacid” because almost allits actions reduce the amount of acid in theduodenum. The only known exception tothis statement is secretin’s pepsigogic activ-ity. Secretin is second only to ACh in pro-moting pepsinogen secretion from the chiefcells of the stomach. Because only smallamounts of secretin are released under nor-mal circumstances, it is doubtful whether se-cretin stimulates pepsin secretion physiolo-gically.

In addition to its physiologic actions onpancreatic and biliary secretion, CCK reg-ulates gallbladder contraction and gastric

emptying. Of the GI peptides, CCK is themost potent regulator of gallbladder contrac-tion; it is approximately 100 times more ef-fective than the gastrin tetrapeptide in con-tracting the gallbladder. CCK causes signi-ficant inhibition of gastric emptying in dosesequal to the D50 of pancreatic secretion.Gastrin also inhibits gastric emptying, butthe effective dose is approximately 6 timesthe D50 for stimulation of acid secretion bygastrin. These data support the conclusionsthat CCK physiologically inhibits gastricemptying and gastrin does not.

CCK also functions to regulate food in-take. It was the first satiety hormone to bediscovered, and this action is fully coveredin Chapter 13.

Several peptides, including secretin andGIP, are enterogastrones. GIP was originallydiscovered because of its ability to inhibitgastric acid secretion, and it may well havebeen the original enterogastrone describedby Ivy and Farrell in 1925. Its action has not

been established as physiologically signific-ant in the innervated stomach. GIP,however, is a strong stimulator of insulin re-lease and is responsible for the fact that anoral glucose load releases more insulin andis metabolized more rapidly than an equalamount of glucose administered intraven-ously.

Motilin stimulates the so-called migratingmotility or myoelectric complex that movesthrough the stomach and small bowel every90 minutes in the fasted GI tract. Its cyclic re-lease into the blood is inhibited by the inges-tion of a meal. This is the only known func-tion of this peptide.

Candidate HormonesEarlier in this chapter, certain peptides isol-ated from digestive tract tissue were men-tioned that may, at a later date, qualify ashormones. These often are referred to as can-didate, or putative, hormones. Many have beenproposed, but interest is greatest for those lis-ted in Table 1-4. Enteroglucagon belongs tothe secretin family. Pancreatic polypeptideand peptide YY (tyrosine-tyrosine) belong toa separate family and are unrelated to eithergastrin or secretin.

TABLE 1-4Candidate Hormones

↓, inhibits; ↑, stimulates; , bicarbonate.

Pancreatic polypeptide was first identifiedas a minor impurity in insulin. It was thenisolated and found to be a linear peptidewith 36 amino acid residues. From aphysiologic viewpoint the most importantaction of pancreatic polypeptide is the in-hibition of both pancreatic bicarbonate andenzyme secretion because this effect has thelowest dose requirement. Most constituents

of a meal release pancreatic polypeptide, andthe serum levels reached are sufficient to in-hibit pancreatic secretion. Because the peakrate of pancreatic secretion during a mealis less than the maximal rate that can beachieved with exogenous stimuli, it is pos-sible that pancreatic polypeptide modulatesthis response under normal conditions. Be-fore it can be concluded that pancreatic poly-peptide is responsible for the physiologic in-hibition of pancreatic secretion, it must beshown that this actually occurs and that pan-creatic polypeptide is the causative agent.The fact that the peptide is located in thepancreas and cannot be removed withoutalso removing its target organ makes thisevidence difficult to obtain.

Peptide YY was discovered in porcinesmall intestine and was named for its N-ter-minal and C-terminal amino acidresidues—both tyrosines. Of its 36 aminoacid residues, 18 are identical to those ofpancreatic polypeptide. Peptide YY is re-

leased by meals, especially by fat. It may ap-pear in plasma in concentrations sufficient toinhibit gastric secretion and emptying andthus qualifies as an enterogastrone. Its effectsdo not appear to be direct in that it doesnot inhibit secretion in response to gastrinor histamine. It does inhibit neurally stimu-lated secretion, but its final status as an en-terogastrone has not been determined.Peptide YY also inhibits intestinal motility,and this effect is believed by some investig-ators to enhance luminal nutrient digestionand absorption.

The enteroglucagons are products of thesame gene processed in the pancreatic alphacell to form glucagon. The intestinal L cellmakes three forms of glucagon, one ofwhich, glucagon-like peptide-1 (GLP-1),may have important physiologic actions.This 30–amino acid peptide is a potent in-sulin releaser, even in the absence of hyper-glycemia, and it also inhibits gastric secre-tion and emptying. GLP-1 may mediate the

so-called ileal brake—the inhibition of gast-ric and pancreatic secretion and motility thatoccurs when lipids and/or carbohydrates areinfused into the ileum in amounts sufficientto cause malabsorption.

NeurocrinesAll GI peptides were once believed to ori-ginate from endocrine cells and therefore tobe either hormones or candidate hormones.With the advent of sophisticated immunocyt-ochemical techniques for tissue localization ofpeptides, it became apparent that many ofthese peptides were contained within thenerves of the gut.

Numerous peptides have been found inboth the brain and the digestive tract mucosa.The first of these to be isolated was substanceP, which in the GI tract stimulates intestinalmotility and gallbladder contraction. Theonly other peptide isolated from both thebrain and gut and known to have an identicalstructure in both sites is neurotensin. Neuro-tensin increases blood glucose by stimulatingglycogenolysis and glucagon release and in-hibiting insulin release. Other peptides havebeen isolated from one site and identified by

radioimmunoassay in the other. These in-clude motilin, CCK, and VIP, which werefirst isolated from the gut. Enkephalin, so-matostatin, and thyrotropin-releasing factorwere first isolated from the brain and laterfound in the gut. Gastrin, VIP, somatostatin,and enkephalin also are present in the nervesof the gut.

Three peptides have important physiolo-gic functions in the gut as neurocrines (listedin Table 1-5). Originally investigatorsthought that VIP was found in gut endocrinecells, but VIP is now known to be localizedwithin the gut exclusively within nerves. Itphysiologically mediates the relaxation of GIsmooth muscle. Smooth muscle is innerv-ated by VIP-containing fibers, and VIP is re-leased during relaxation. VIP relaxes smoothmuscle, and VIP antiserum blocks neurallyinduced relaxation. In addition, strong evid-ence indicates that VIP physiologically me-diates relaxation of smooth muscle in bloodvessels and thus may be responsible for vas-

odilation. Besides these effects, VIP hasmany of the actions of its relatives, secretinand GIP, when it is injected into the blood-stream. It stimulates pancreatic secretion, in-hibits gastric secretion, and stimulates intest-inal secretion. Many of the effects of VIP onsmooth muscle are mediated by nitric oxide(NO); VIP stimulates the synthesis of this po-tent smooth muscle relaxant.

TABLE 1-5Neurocrines

Peptide Location ActionVIP Mucosa and

muscle of gutRelaxation of gutsmooth muscle

GRP orbombesin

Gastric mucosa ↑Gastrin release

EnkephalinsMucosa andmuscle of gut

↑Smooth muscle tone

GRP, gastrin-releasing peptide; VIP, vasoactive in-testinal peptide; ↑, stimulates.

Numerous biologically active peptideshave been isolated from amphibian skin andlater found to have mammalian counter-parts. One of these, called bombesin after thespecies of frog from which it was isolated, isa potent releaser of gastrin. The mammaliancounterpart of bombesin is gastrin-releasingpeptide (GRP), which has been found in thenerves of the gastric mucosa. GRP is releasedby vagal stimulation and mediates the vagalrelease of gastrin. Luminal protein digestionproducts may also stimulate gastrin releasethrough a GRP-mediated mechanism.

Two pentapeptides isolated from pig andcalf brains activate opiate receptors and arecalled enkephalins. They are identical exceptthat the C-terminal amino acid is methioninein one and leucine in the other. These com-pounds are present in nerves within boththe smooth muscle and the mucosa of theGI tract. Opiate receptors on circular smoothmuscle cells mediate contraction, and leuen-kephalin and metenkephalin cause contrac-

tion of the lower esophageal, pyloric, andileocecal sphincters. The enkephalins func-tion physiologically at these sites and alsomay be an intricate part of the peristalticmechanism. The effect of opiates on intest-inal motility is to slow transit of materialthrough the gut. These peptides also inhibitintestinal secretion. The combination ofthese actions probably accounts for the ef-fectiveness of opiates in treating diarrhea.

Absent from Table 1-5 is pituitary aden-ylate cyclase–activating peptide (PACAP),the newest member of the secretin family. Ifsomatostatin is blocked, injection of PACAPstimulates the release of histamine from ECLcells and therefore stimulates acid secretion.PACAP also stimulates ECL cell growth, soits actions are similar to those of gastrin. Itmay be a significant neural mediator of ECLcell function, but direct evidence that ECLcells are innervated by PACAP-containingfibers is missing.

ParacrinesParacrines are like hormones in that they arereleased from endocrine cells. They are sim-ilar to neurocrines because they interact withreceptors close to the point of their release.The biologic significance of an endocrine canbe assessed by correlating physiologic eventswith changes in blood levels of the hormonein question. Because the area of release ofboth paracrines and neurocrines is restricted,no comparable methods are available forproving the biologic significance of one ofthese agents. Current experiments examinethe effects of specific pharmacologic blockersor antisera directed toward these substances.In vitro perfused organs are also useful in ex-amining paracrine mediators. These systemsallow an investigator to collect and assaysmall volumes of venous perfusate for theagent in question.

One GI peptide, somatostatin, functionsphysiologically as a paracrine to inhibit gast-rin release and gastric acid secretion. So-matostatin was first isolated from the hypo-thalamus as a growth hormone re-lease–inhibitory factor. It has since beenshown to exist throughout the gastric andduodenal mucosa and the pancreas in highconcentrations and to inhibit the release ofall gut hormones. Somatostatin mediates theinhibition of gastrin release occurring whenthe antral mucosa is acidified. Somatostatinalso directly inhibits acid secretion from theparietal cells and the release of histaminefrom ECL cells. These are importantphysiologic actions of this peptide.

Histamine is a second important paracrineagent. Produced in ECL cells by the de-carboxylation of histidine, histamine is re-leased by gastrin and then stimulates acidsecretion from the gastric parietal cells.Histamine also potentiates the action of gast-rin and ACh on acid secretion. This is why

the histamine H2 receptor–blocking drugs,such as cimetidine (Tagamet) and ranitidine(Zantac), are effective inhibitors of acid se-cretion regardless of the stimulus. Althoughparietal cells respond directly to gastrin, re-leased histamine accounts for most of thestimulation of acid secretion by this hor-mone.

CLINICALAPPLICATIONSNon–beta cell tumors of the pan-creas or duodenal tumors mayproduce gastrin and continuallyrelease it into the blood. This dis-ease is known as gastrinoma orZollinger-Ellison syndrome. Thetumors are small and difficult todefine and resect; if metastasiz-ing, they grow slowly. Gastrin isreleased from these tumors at ahigh spontaneous rate that is notaltered by feeding. The hyper-

gastrinemia results in hyperse-cretion of gastric acid throughtwo mechanisms. First, thetrophic action of gastrin leads toincreased parietal cell mass andacid secretory capacity. Second,increased serum gastrin levelsconstantly stimulate secretionfrom the hyperplastic mucosa.The complications of this dis-ease—fulminant peptic ulcera-tion, diarrhea, steatorrhea, andhypokalemia—are caused by thepresence of large amounts ofacid in the small bowel. The con-tinual presence of acid in theduodenum overwhelms theneutralizing ability of the pan-creas, erodes the mucosa, andproduces ulcers. In largeamounts, gastrin inhibits absorp-tion of fluid and electrolytes by

the intestine and thereby adds tothe large volumes of fluid (up to10 liters [L]/day) entering the in-testine. Increased intestinaltransit probably also contributesto the diarrhea. Steatorrhea isproduced by inactivation of pan-creatic lipase and precipitation ofbile salts at a low luminal pH. Be-cause the tumors are difficult toresect and the clinical manifest-ations are caused by hypersecre-tion of gastric acid, the preferredsurgical treatment is removal ofthe target organ (the stomach).Although gastrin levels remainelevated, total gastrectomy stopsthe ulceration and diarrhea. Thisdisease also may be treated non-surgically with some of thepowerful new drugs that inhibitacid secretion (see Chapter 8).

The only other clinical condi-tion attributed to the overpro-duction of a GI peptide concernsVIP. Pancreatic cholera, or wa-tery diarrhea syndrome, is a fre-quently lethal disease resultingfrom the secretion of a peptideby a pancreatic islet cell tumor.This peptide is a potent stimulusfor intestinal secretion of the flu-id and electrolytes that producethe copious diarrhea. VIP hasbeen identified in both the tumortissue and the serum of these pa-tients. The ability of VIP to stim-ulate cholera-like fluid secretionfrom the intestine indicates thatit is responsible for this disease.

CLINICAL TESTS

Gastrin is routinely measured byradioimmunoassay in clinicallaboratories. Normal serum gast-rin values must be set by eachlaboratory for its particular as-say. If the normal mean serumgastrin concentration is taken as50 picograms (pg)/milliliter(mL), serum gastrin in fastingpatients with gastrinoma usuallyexceeds 200 pg/mL. The degreeof overlap between patients withgastrinoma and those with or-dinary duodenal ulcer diseasemeans that specific tests are re-quired to diagnose the gast-rinoma.

The tests most widely used inthe evaluation of hypergast-rinemia include stimulation withprotein meals, intravenous calci-um infusion, and secretin infu-

sion. Patients with Zollinger-El-lison syndrome may not releasegastrin in detectable amounts inresponse to food. The reasonmay be the low pH of gastriccontents that is caused by ongo-ing acid secretion stimulated bypreexisting high serum gastrinlevels. Acid in the antrum inhib-its gastrin release, and any gast-rin that could be released wouldbe difficult to detect against thealready high serum levels.

Patients with gastrinoma mayhave an exaggerated acid secret-ory response to calcium infu-sions that is caused by the releaseof gastrin from tumor tissue.This test is run by infusing 5 mil-ligrams (mg) of ionizable calci-um/kilogram (kg)/hour as calci-um gluconate for 3 hours while

simultaneously measuring acidsecretion and collecting bloodsamples at hourly intervals forgastrin determination. Peak gast-rin responses are usually ob-tained 3 hours after calcium in-fusion is begun. In most patientswith gastrinoma, serum gastrinconcentrations will at leastdouble, so the gastrin values willbe more than 500 pg/mL. Pa-tients with ordinary ulcer diseasemay show moderate increases inserum gastrin with calcium infu-sion, but absolute gastrin valuesafter stimulation seldom exceed200 to 300 pg/mL.

The most specific and easiesttest to administer for gastrinomais secretin injection. Secretin in-hibits antral gastrin release, yet itstimulates tumor gastrin release

in almost all patients with gast-rinoma. Secretin (1 unit [U]/kg)is given as a rapid intravenousinjection and causes a peak in-crease in serum gastrin 5 to 10minutes later. In a patient withdefinitely increased basal serumgastrin and acid hypersecretion,a doubling of serum gastrin at 5to 10 minutes strongly indicatesthe presence of a gastrinoma.

Summary1. The functions of the GI tract are regulatedby mediators acting as hormones (endo-crines), paracrines, or neurocrines.2. Two chemically related families of peptidesare responsible for much of the regulation ofGI function. These are gastrin/CCK peptidesand a second group containing secretin, VIP,GIP, and glucagon.3. The GI hormones are located in endocrinecells scattered throughout the mucosa and re-leased by chemicals in food, neural activity, orphysical distention.4. The GI peptides have many pharmacologicactions, but only a few of these are physiolo-gically significant.5. Gastrin, CCK, secretin, GIP, and motilin areimportant GI hormones.6. Somatostatin and histamine have import-ant functions as paracrine agents.

7. VIP, bombesin (or GRP), and the enkeph-alins are released from nerves and mediatemany important functions of the digestivetract.

KEY WORDS ANDCONCEPTSEndocrines/hormonesParacrinesNeurocrinesAcetylcholineSecretinGastrinCholecystokininEnterogastroneGastric inhibitory peptideMotilinGastrin IIVasoactive intestinal peptideGlucagonEnteroglucagonG-GlyCCK-B receptor

Amine precursor uptake de-carboxylationEnterochromaffin-like cellsPancreatic polypeptidePeptide YYGlucagon-like peptide-1SomatostatinHistamine

Suggested ReadingsChao, C., Hellmich, M. R., Gastrointestinal peptides:

gastrin, cholecystokinin, somatostatin, andghrelinJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 1. San Diego: El-sevier, 2012.

Gomez, G. A., Englander, E. W., Greeley, G. H., Jr.,Postpyloric gastrointestinal peptidesJohnson, L.R., eds. Physiology of the Gastrointestinal Tract,ed 5, vol 1. San Diego: Elsevier, 2012.

Johnson, L. R. Regulation of gastrointestinal mucosalgrowth. In Johnson L. R., ed. : Physiology of the

Gastrointestinal Tract, ed 3, New York: RavenPress, 1994.

Makhlouf G. M., ed. Handbook of Physiology, Sec-tion 6: The Gastrointestinal System, vol. 2: Neuraland Endocrine Biology. Bethesda, MD: AmericanPhysiological Society, 1989.

Modlin, I. M., Sachs, G. Acid Related Diseases. Milan:Schnetztor Verlag Gmbh D-Konstanz; 1998.

Pearse, A. G. E., Takor, T. Embryology of the diffuseneuroendocrine system and its relationship to thecommon peptides. Fed Proc. 1979; 38:2288–2294.

Rozengurt, E., Walsh, J. H. Gastrin, CCK, signaling,and cancer. Annu Rev Physiol. 2001; 63:49–76.

Solcia, E., Capella, C., Buffa, R., et al. Endocrine cellsof the digestive system. In Johnson L. R., ed. :Physiology of the Gastrointestinal Tract, ed 2, NewYork: Raven Press, 1987.

Walsh, J. H. Gastrointestinal hormones. In Johnson L.R., ed. : Physiology of the Gastrointestinal Tract, ed3, New York: Raven Press, 1994.

Walsh, J. H., Grossman, M. I. Gastrin. N Engl J Med.1975; 292:1324–1332. [1337–1384].

Walsh, J. H., Grossman, M. I. The Zollinger-Ellisonsyndrome. Gastroenterology. 1973; 65:140–165.

Regulation

Nerves and SmoothMuscle

Object ives

Understand the anatomy and functions ofthe enteric nervous system and its relation-ship with the parasympathetic and sym-pathetic systems.Describe the anatomy and types of con-tractions of smooth muscle cells.

Explain the role of calcium ion in the con-traction and relaxation of smooth musclecells.Understand the roles of the interstitialcells of Cajal and slow waves in the con-traction of smooth muscle cells.

Secretory, motility, and absorptive functionsof the gastrointestinal (GI) system are integ-rated to digest food and absorb nutrientsand to maintain homeostasis between meals.This integration is mediated by regulatorysystems that monitor events within the body(primarily the GI tract) and in the externalenvironment. In Chapter 1, the importantmediators released from endocrine, parac-rine, and neurocrine cells are discussed. Inthis chapter, the role of the nervous system isconsidered in more detail.

Although the regulatory systems act to in-tegrate the activities of the GI system, mostsecretory, absorptive, and muscle cells pos-sess intrinsic activities that give them a de-gree of autonomy. Thus function arises outof the interaction of regulatory systems andlocal intrinsic properties. The basic proper-ties and intrinsic activities of each type ofsecretory and absorptive cell are discussedin separate chapters that deal with the se-cretion and absorption of specific chemicals.The basic properties and intrinsic activitiesof the smooth muscle cells are discussed inthis chapter.

Anatomy of theAutonomic NervousSystemThe GI tract is innervated by the autonomicnervous system (ANS). It is called the ANSbecause, under normal circumstances, peopleneither are conscious of its activities nor exertany willful control over them. The ANS canbe divided into the extrinsic nervous systemand the intrinsic, or enteric, nervous system.

The extrinsic nervous system is in turn di-vided into parasympathetic and sympatheticbranches ( Fig. 2-1). Parasympathetic innerv-ation is supplied primarily by the vagus andpelvic nerves. Long preganglionic axons arisefrom cell bodies within the medulla of thebrain and the sacral region of the spinal cord.These preganglionic nerves enter the variousorgans of the GI tract, where they synapse

mainly with cells of the enteric nervous sys-tem ( Fig. 2-2). In addition, these same nervebundles contain many afferent nerves whosereceptors lie within the various tissues of thegut. These nerves project to the brain andspinal cord to provide sensory input for in-tegration. Approximately 75% of the fiberswithin the vagus nerve are afferent. Thus in-formation can be relayed from the GI tract tothe medulla and integrated, and a messagecan be sent back to the tract that may influen-ce motility, secretion, or the release of a hor-mone. These long or vagovagal reflexes playimportant roles in regulating GI functions.

FIGURE 2-1 Extrinsic branches of theautonomic nervous system. A, Parasym-pathetic. Dashed lines indicate the choliner-gic innervation of striated muscle in the eso-phagus and external anal sphincter. Solidlines indicate the afferent and preganglionicefferent innervation of the rest of thegastrointestinal tract. B, Sympathetic. Solidlines denote the afferent and preganglionic

efferent connections between the spinalcord and the prevertebral ganglia. Dashedlines indicate the afferent and postganglion-ic efferent innervation. CG, celiac ganglion;IMG, inferior mesenteric ganglion; SMG, su-perior mesenteric ganglion.

FIGURE 2-2 The integration of the extrins-ic (parasympathetic and sympathetic)nervous system with the enteric (myentericand submucosal plexuses) nervous system.The preganglionic fibers of the parasym-

pathetic synapse with ganglion cells locatedin the enteric nervous system. Their cellbodies, in turn, send signals to smoothmuscle, secretory, and endocrine cells.They also receive information from recept-ors located in the mucosa and in the smoothmuscle that is relayed to higher centers viavagal afferents. This may result in vagovag-al (long) reflexes. Postganglionic efferentfibers from the sympathetic ganglia innerv-ate the elements of the enteric system, butthey also innervate smooth muscle, bloodvessels, and secretory cells directly. Theenteric nervous system relays informationup and down the length of the gastrointest-inal tract, and this may result in short or in-trinsic reflexes. (Reprinted with permission from John-

son LR. Essential Medical Physiology, 3rd ed. Philad-

elphia, Academic Press, 2003.)

Sympathetic innervation is supplied bynerves that run between the spinal cord andthe prevertebral ganglia and between theseganglia and the organs of the gut. Pregan-glionic efferent fibers arise within the spinal

cord and end in the prevertebral ganglia.Postganglionic fibers from these gangliathen innervate primarily the elements of theenteric nervous system (see Fig. 2-1). Fewfibers end directly on secretory, absorptive,or muscle cells. Afferent fibers also arepresent within the sympathetic division.These nerves project back to the prevertebralganglia and/or the spinal cord. Thus anabundance of sensory information also isavailable via these nerves.

Elements of the intrinsic, or enteric,nervous system are grouped into severalanatomically distinct networks, of which themyenteric and submucosal plexuses (seeFig. 2-2) are the most prominent. These plex-uses consist of nerve cell bodies, axons,dendrites, and nerve endings. Processesfrom the neurons of the plexuses do not justinnervate target cells such as smooth muscle,secretory cells, and absorptive cells. Theyalso connect to sensory receptors and inter-digitate with processes from other neurons

located both inside and outside the plexus.Thus pathways within the enteric nervoussystem can be multisynaptic, and integrationof activities can take place entirely within theenteric nervous system (see Fig. 2-2), as wellas in the ganglia of the extrinsic nerves, thespinal cord, and the brainstem.

Many chemicals serve as neurocrineswithin the ANS. Several of these chemicalshave been localized within specific path-ways, and a few have defined physiologicroles. Most of the extrinsic, preganglionic,efferent fibers contain acetylcholine (ACh).This transmitter exerts its action on neuronscontained within the prevertebral gangliaand enteric nervous system. Norepineph-rine is found in many nerve endings of thepostganglionic efferent nerves of the sym-pathetic nervous system. This transmitteralso exerts its effects primarily on neurons ofthe enteric nervous system. Within the en-teric nervous system, ACh, serotonin, vaso-active intestinal peptide (VIP), nitric oxide

(NO), and somatostatin have been localizedto interneurons. ACh and the tachykinins(TKs) (e.g., substance P) have been localizedto nerves that are excitatory to the muscle;VIP and NO have been localized to inhibit-ory nerves to the muscle. In many instances,more than one transmitter can be localized tothe same nerve. The goals of mapping neur-al circuits within the extrinsic and entericnervous system and elucidating their func-tions are far from complete.

NeurohumoralRegulation ofGastrointestinal FunctionAlthough it is convenient to discuss the ANSand the endocrine/paracrine systems separ-ately, it is important to understand that theydo not function independently of one another.Rather, the regulatory systems interact to con-trol secretion, absorption, and motility. Spe-cific examples of such regulation are given insubsequent chapters (see Figs. 8-10 and 9-7 forexamples). The targets, be they secretory, ab-sorptive, or smooth muscle cells, have a cer-tain resting output that is modulated by bothneurally released chemicals and humorallydelivered chemicals. These chemicals are re-leased from nerve endings and glandular cellsin response to various stimuli that act on spe-cific receptors. The sources of these stimuli

can be either in the environment or withinthe body. For example, seeing or smellingappetizing food alters many aspects of GIfunction, as does the presence of many food-stuffs and products of digestion within thelumen of the stomach and intestine. In manycases, the stimuli result from the secretoryand motor functions of the target cells them-selves. Whatever their source, these stimuliinitiate inputs that are integrated in the neur-al and endocrine systems to produce outputsthat appropriately regulate the functions ofthe target cells.

Anatomy of the SmoothMuscle CellThe contractile tissue of the GI tract is madeup of smooth muscle cells, except in thepharynx, orad third of the esophagus, and ex-ternal anal sphincter. The smooth muscle cellsfound in each region of the GI tract exhibitfunctional and structural differences. Thesespecial features are considered in subsequentchapters. However, certain basic propertiesare common to all smooth muscle cells. Thecells, which are 4 to 10 micrometers (µm)wide and 50 to 200 µm long, are small whencompared with skeletal muscle cells. A dis-tinguishing feature of these cells is that thecontractile elements are not arranged in or-derly sarcomeres as in skeletal muscle ( Fig.2-3). Thus the cells have no striations. Manyof the contractile proteins found in striatedmuscle also exist in smooth muscle, although

they differ in isoform and in relativeamounts. Actin, along with tropomyosin, isthe main constituent of thin filaments,whereas myosin is the main constituent ofthick filaments. Compared with skeletalmuscle, smooth muscle contains less myosin,much more actin, and little if any troponin.The apparent ratio of thin to thick filamentsin smooth muscles is 12:1 to 18:1, rather than2:1 as in skeletal muscle. In addition to thethick and thin filaments, smooth muscle cellscontain a third network of filaments thatform an internal “skeleton.” These interme-diate filaments, along with their associateddense bodies, may serve as anchor points forthe contractile filaments and may modulatecontractile activity.

FIGURE 2-3 Intracellular structural spe-cializations of a smooth muscle cell. N, nuc-leus. (Adapted from Schiller LR: Motor function of the

stomach. In Sleisenger MH, Fordtran JS [eds]:

Gastrointestinal Disease. Philadelphia, Saunders, 1983.)

Smooth muscle cells of the GI tract aregrouped into branching bundles, or fasciae,that are surrounded by connective tissuesheets. These fasciae, organized into muscu-lar coats, can serve as the effector units be-cause smooth muscle cells of the gut aremostly of the “unitary” type ( Fig. 2-4). Indi-vidual cells are functionally coupled to oneanother so that the contractions of a bundleof muscle are synchronous. In most tissues,this coupling is the result of actual fusionof apposing membranes in the form of gapjunctions or nexuses. These junctions serveas areas of low resistance for the spread ofexcitation from one cell to another. Notevery smooth muscle cell is innervated.Nerve axons enter the muscle bundles and

release neurotransmitters from swellingsalong their length.

FIGURE 2-4 Anatomic features of “unitary”smooth muscle. Neurotransmitter is re-leased from varicosities along the nervetrunk. Other chemicals arrive via endocrineand paracrine routes. The influence of thesesubstances on one muscle cell is thentransmitted to other cells via nexuses.

These swellings usually are some distancefrom the muscle cells so that no discreteneuromuscular junctions exist. Thus the

neurotransmitters probably act on only afew of the muscle cells or on interstitial cellsof Cajal (ICCs), which in turn form junctionswith muscle cells. The influence of the trans-mitters must then be communicated fromone smooth muscle cell to the next.

Smooth MuscleContractionThe time course of contractions amongsmooth muscles in the GI tract has remark-able heterogeneity. Some muscles, such asthose found in the body of the esophagus,small bowel, and gastric antrum, contract andrelax in a matter of seconds (phasic contrac-tions). Other smooth muscles, such as thosefound in the lower esophageal sphincter, oradstomach, and ileocecal and internal analsphincters, show sustained contractions thatlast from minutes to hours. These muscles ex-hibit what are called tonic contractions. Asdiscussed in subsequent chapters, the type ofcontraction, whether phasic or tonic, is gov-erned by the smooth muscle cells themselvesor by ICCs in association with smooth musclecells. It does not depend on neural or hormon-al input. Neurocrines, endocrines, and parac-

rines are important because they modulatethe basic contractile activity, so that the amp-litude of the contractions of phasic musclesvaries and the tone of the tonic muscles in-creases or decreases.

As in striated muscle, contractile activityof smooth muscle, especially those musclesthat contract phasically, is modulated byfluctuating levels of free intracellular calci-um (Ca2+). At low levels (less than 10–7 molar[M]) of Ca2+, interaction of the contractileproteins does not occur. At higher levels ofCa2+, proteins interact and contractions oc-cur. The prevailing theory to explain howCa2+ brings about contraction is that the Ca2+,combined with the Ca2+-binding proteincalmodulin, activates a protein kinase thatbrings about the specific phosphorylation ofone of the components of myosin ( Fig. 2-5).Myosin in its phosphorylated form then in-teracts with actin to cause contraction, whichis fueled by the splitting of adenosine tri-

phosphate (ATP). When the intracellularlevels of Ca2+ fall, the myosin is dephos-phorylated by a specific phosphatase. Thisleads to a cessation of the interactionbetween the contractile proteins, and musclerelaxation occurs. In smooth muscles thatcontract tonically, the exact mechanism forthe maintenance of tone is not known. Whatis known is that tone can be maintained atlow levels of phosphorylation of myosin andof ATP utilization. In addition, it is becom-ing apparent that smooth muscle contractionis regulated not only by levels of Ca2+ butalso by processes that regulate the activityof the phosphatase(s) that dephosphorylatesmyosin, thereby altering the Ca2+ sensitivityof the contractile process.

FIGURE 2-5 Biochemical events insmooth muscle contraction. An increase inthe levels of calcium (Ca2+) activates theenzyme myosin light chain kinase (MLCK),which phosphorylates myosin. Phos-phorylated myosin (Myosin P) interacts withactin to cause muscle contraction and aden-osine triphosphate (ATP) consumption.When Ca2+ levels fall, the kinase becomesinactive, and the activity of myosin lightchain phosphatase (MLCP) dominates. My-

osin P is dephosphorylated, and the musclerelaxes. The activities of both MLCK andMLCP can be modulated by kinases and/orsecond messengers to influence calciumsensitivity of the contractile process. ADP,adenosine diphosphate; CaM, calmodulin;Pi, inorganic phosphate.

The exact source of the Ca2+ that particip-ates in the contractile process is not certainand appears to vary from one muscle to an-other. In many muscles (e.g., muscle fromthe body of the esophagus), Ca2+ enters thecells from the extracellular fluid or frompools of Ca2+ that are tightly bound to thesmooth muscle cell membranes or containedin caveolae (see Fig. 2-3). Influx of Ca2+ fromthese sites is regulated by permeabilitychanges of the membrane that also causecharacteristic electrical activities (see the fol-lowing paragraph). In other muscles (e.g.,muscle from the lower esophageal sphinc-ter), Ca2+ is sequestered in intracellular struc-

tures called the sarcoplasmic reticulum (seeFig. 2-4) and is released in response to elec-trical events of the plasma membrane or toagonist-induced increases in inositol triphos-phate, or to both. In addition to these sourcesfor Ca2+, mechanisms also exist for the expul-sion of Ca2+ from the cells and for reuptakeinto the sarcoplasmic reticulum.

Increases in free intracellular Ca2+ most of-ten are related to electrical activities of thesmooth muscle cell membranes. In phasic-ally active muscle, Ca2+ enters the cell by wayof voltage-dependent Ca2+ channels. Whenthese channels are activated, rapid transientsin membrane potential occur; these arecalled action or spike potentials (see Fig.5-6). In many physically active muscles,these spike potentials do not arise from astable resting membrane potential. Rather,they are superimposed on relatively slow (3to 12 cycles/minute) but regular oscillationsin membrane potential.

These potential changes, called slowwaves, do not in themselves cause signific-ant contractions. They set the timing,however, for when spike potentials can oc-cur because spikes are seen only during thepeak of depolarization of the slow wave.

The genesis of slow waves appears to lie incomplex interactions among smooth musclecells and specialized cells called interstitialcells of Cajal (ICCs) ( Fig. 2-6). In all regionsof the GI tract from which slow waves are re-corded, ICCs are present and are connectedto one another to form a three-dimensionalnetwork within and/or between the smoothmuscle layers. These cells not only commu-nicate with one another but also form gapjunctions with smooth muscle cells. SomeICCs appear to be interposed between en-teric nerve endings and smooth muscle cellsand may be involved in neural modulationof smooth muscle activity rather than in slowwave generation. Isolated ICCs exhibit mem-brane properties that could provide the

pacemaker activity responsible for the gen-eration of slow waves. This activity spreadsinto and affects the smooth muscle cells.Both slow waves and spike potentials arerecorded from smooth muscle cells that arecoupled to ICCs, but slow waves are absentfrom intestinal smooth muscle devoid ofICCs (see Fig. 2-6).

FIGURE 2-6 Top, Interactions among in-terstitial cells of Cajal (ICCs), smoothmuscle cells, and nerves. Pacemaker cur-rent leading to slow waves appears to ori-

ginate in the ICC network. Slow waves act-ively propagate within the ICC network andare passively conducted into the smoothmuscle. Other ICCs appear to be interposedbetween nerve endings and smooth musclecells; they may be involved in neuromodula-tion. Bottom, Recordings of electrical activ-ity from the small intestine of a normalmouse (A) and a mouse deficient in ICCs(B). Note the absence of slow waves in B.(Modified from Horowitz B, Ward SM, Sanders KM: Cellu-

lar and molecular basis for electrical rhythmicity in

gastrointestinal muscles. Annu Rev Physiol 61:19-43,

1999.)

Slow waves are extremely regular and areonly minimally influenced by neural or hor-monal activities, although they are influen-ced by body temperature and metabolicactivity. The higher the activity, the higheris the frequency of slow waves. Conversely,the occurrence of spike potentials dependsheavily on neural and hormonal activities.

An excitatory endocrine, paracrine, orneurocrine acts on a receptor on the smooth

muscle cell membrane to induce spike po-tentials in those cells and in adjacent cellsthat are coupled to one another. The spikepotentials lead to an increase in intercellularfree Ca2+ levels. The Ca2+ then acts via myos-in light chain kinase to induce contraction.In contrast, an inhibitory mediator acts withits receptor on that same membrane. In thiscase, however, the response is an inhibitionof spike potentials or a hyperpolarization ofthe cell membrane or both. This results in adecrease in intracellular free Ca2+ and sub-sequent relaxation. In addition, evidence in-dicates that activation of cell receptors alsocan modulate contractile activity throughmechanisms not involving the Ca2+-myosinphosphorylation pathway. Whatever themechanism, it is the interplay of these excit-atory and inhibitory mediators on the bas-al activity of the muscle that determines themotility functions of the various organs ofthe gut.

Summary1. The regulation of GI function results froman interplay of neural and hormonal influen-ces on effector cells that have intrinsic activit-ies.2. The GI tract is innervated by the ANS,which is composed of nerves that are extrinsicand nerves that are intrinsic to the tract.3. Extrinsic nerves are distributed to the GItract through both parasympathetic and sym-pathetic pathways.4. Intrinsic nerves are grouped into severalnerve plexuses, of which the myenteric andsubmucosal plexuses are the most prominent.Nerves in the plexuses receive input from re-ceptors within the GI tract and from extrinsicnerves. This input can be integrated withinthe intrinsic nerves such that coordinatedactivities can be effected.5. ACh is one of the major excitatory neur-otransmitters, and NO and VIP are two of

the major inhibitory neurotransmitters at ef-fector cells. Serotonin and somatostatin aretwo important neurotransmitters of intrinsicinterneurons.6. Striated muscle comprises the muscu-lature of the pharynx, the oral half of theesophagus, and the external anal sphincter.Smooth muscle makes up the musculature ofthe rest of the GI tract.7. Adjacent smooth muscle cells are electric-ally coupled to one another and contract syn-chronously when stimulated. Some smoothmuscles contract tonically, whereas otherscontract phasically.8. In phasically active muscle, stimulation in-duces a rise in intracellular Ca2+, which inturn induces phosphorylation of the20,000-dalton light chain of myosin. ATP issplit, and the muscle contracts as the phos-phorylated myosin (myosin P) interacts withactin. Ca2+ levels fall, myosin is dephos-phorylated, and relaxation occurs. In tonic-ally active muscles, contraction can be main-

tained at low levels of phosphorylation andATP utilization.9. Periodic membrane depolarizations andrepolarizations, called slow waves, are majordeterminants of the phasic nature of contrac-tion. Slow wave activity results from ioniccurrents initiated through the interactions ofthe ICCs with smooth muscle cells.

KEY WORDS ANDCONCEPTSAutonomic nervous systemExtrinsic nervous systemParasympathetic innervationVagovagal reflexesSympathetic innervationIntrinsic/enteric nervous systemMyenteric/submucosal plexusesNeurocrinesAcetylcholineNorepinephrineSerotoninVasoactive intestinal peptide

Nitric oxideSomatostatinSubstance PSmooth muscle cellsFasciaePhasic contractionsTonic contractionsCalciumAdenosine triphosphateAction/spike potentialsSlow wavesInterstitial cells of CajalContractionRelaxation

Suggested ReadingsBitar, K. N., Gilmont, R. R., Raghavan, S., Somara, S.,

Cellular physiology of gastrointestinal smoothmuscleJohnson, L. R., eds. Physiology of the

Gastrointestinal Tract, ed 5, vol 1. San Diego: El-sevier, 2012.

Murphy, R. A. Muscle in the walls of hollow organs.In Berne R. M., Levy M. N., eds. : Principles ofPhysiology, ed 3, St. Louis: Mosby, 2000.

Pfitzer, G. Signal transduction in smooth muscle. In-vited review: regulation of myosin phosphoryla-tion in smooth muscle. J Appl Physiol. 2001;91:497–503.

Roman, C., Gonella, J., Extrinsic control of digestivetract motilityJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 2, vol 1. New York:Raven Press, 1987.

Sanders, K. M., Koh, S. D., Ward, S. M., Organizationand electrophysiology of interstitial cells of Cajaland smooth muscle cells in the gastrointestinaltractJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 1. San Diego: El-sevier, 2012.

Wood, J. D., Integrative functions of the entericnervous systemJohnson, L. R., eds. Physiology ofthe Gastrointestinal Tract, ed 5, vol 1. San Diego:Elsevier, 2012.

Swallowing

Object ives

Describe the oral and pharyngeal eventstaking place during a swallow.Describe the pressures within the eso-phagus and oral stomach at rest and duringa swallow.Explain the regulation involved during aswallow, including its initiation and peri-stalsis through the esophagus.Understand the process of receptive relax-ation of the oral stomach, its function, andregulation.

Understand gastric esophageal reflux dis-ease (GERD) and its causes.

Swallowing consists of chewing, a pharyn-geal phase, movement of material throughthe esophagus, and the relaxation of thestomach to receive the ingested material.Swallowing is almost purely a motility func-tion. Digestion and absorption are minimal,in part because transport of the bolus intothe stomach takes only seconds.

ChewingChewing has three major functions: (1) it facil-itates swallowing by reducing the size of in-gested particles and thus also prevents dam-age to the lining of the pharynx and esophag-us; (2) it mixes food with saliva, which ex-poses the food to digestive enzymes and lub-ricates it; (3) it increases the surface area of in-gested material and thereby increases the rateat which it can be digested.

The act of chewing is both voluntary andinvoluntary, and most of the time it proceedsby reflexes void of conscious input. The chew-ing reflex is initiated by food in the mouththat inhibits muscles of mastication andcauses the jaw to drop. A subsequent stretchreflex of the jaw muscles produces a contrac-tion that automatically raises the jaw andcloses the teeth on the bolus of food. Com-pression of the bolus on the mucosal surface

of the mouth inhibits the jaw muscles to re-peat the process.

Pharyngeal PhaseNormally liquids are propelled immediatelyfrom the mouth to the oropharynx and areswallowed. Swallowing is initiated bypropulsion of material into the oropharynxprimarily by movements of the tongue. Theportion of solid material to be swallowed isseparated from other material in the mouth soit lies in a chamber created by placing the tipof the tongue against the hard palate ( Fig. 3-1,A). The material is propelled by elevation andretraction of the tongue against the palate. Asthe material passes from the oral cavity intothe oropharynx, the nasopharynx is closed bymovement of the soft palate and contractionof the superior constrictor muscles of thepharynx ( Fig. 3-1, B). Simultaneously, res-piration is inhibited, and contraction of thelaryngeal muscles closes the glottis and raisesthe larynx. The bolus is propelled throughthe pharynx by a peristaltic contraction that

begins in the superior constrictor and pro-gresses through the middle and inferior con-strictor muscles of the pharynx ( Fig. 3-1, C).These contractions, along with relaxation ofthe upper esophageal sphincter (UES), pro-pel the bolus into the esophagus ( Fig. 3-1,D).

FIGURE 3-1 Oral and pharyngeal eventsduring swallowing. A, The food bolus (F) to

be swallowed is propelled into the pharynxby placement of the tongue (T) on the roofof the hard palate. E, esophagus; Ep, epi-glottis; Tr, trachea. B, Further propulsion iscaused by movement of the more distal re-gions of the tongue against the palate. Con-traction of the upper constrictors of thepharynx and movement of the soft palateseparate the oropharynx from thenasopharynx. C, Propulsion through the up-per esophageal sphincter is accomplishedby contraction of the middle and lower con-strictors of the pharynx and by relaxation ofthe cricopharyngeal muscle. Upward move-ment of the glottis and downward movementof the epiglottis seal off the trachea. D, Thebolus is now in the esophagus and is pro-pelled into the stomach by a peristaltic con-traction.

The oral and pharyngeal phases of swal-lowing are rapid, taking less than 1 second.Swallowing can be initiated voluntarily, butthese efforts fail unless something, at leasta small amount of saliva, triggers the swal-lowing reflex. Once initiated, however, swal-

lowing proceeds as a coordinated involun-tary reflex. Coordination is central in origin,and an area within the reticular formationof the brainstem has been identified as theswallowing center. Afferent impulses fromthe pharynx are directed toward this center,which serves to coordinate the activity ofother areas of the brain such as the nucleiof the trigeminal, facial, and hypoglossalnerves, as well as the nucleus ambiguus (Fig. 3-2). Efferent impulses from the centerare distributed to the pharynx via nervesfrom the nucleus ambiguus. The impulsesappear to be sequential, so the pharyngealmusculature is activated in a proximal-to-distal manner. This sequencing accounts forthe peristaltic nature of the pharyngeal con-tractions. The center also appears to interactwith other areas of the brain involved withrespiration and speech. Injury to the swal-lowing center produces abnormalities in thepharyngeal component of swallowing.

FIGURE 3-2 Control of pharyngeal andesophageal peristalsis. Sensory input fromthe pharynx activates an area in the medulla(the swallowing center). This center servesto coordinate activation of the vagal nucleiwith other centers such as the respiratorycenters. Muscles of the pharynx and striatedareas of the esophagus are activated by thecenter via the nucleus ambiguus. Areas ofthe smooth muscle are activated via thedorsal motor nucleus. Peristalsis resultsfrom sequential activation of the muscles ofthe pharynx and esophagus by sequentialneural impulses from the center. The areaenclosed within the circle is shown in moredetail in Figure 3-4.

Esophageal PeristalsisThe esophagus propels material from thepharynx to the stomach. This propulsion isaccomplished by coordinated contractions ofthe muscular layers of the body of the eso-phagus. Because a large segment of the eso-phagus is located in the thorax, where thepressure is lower than in the pharynx andstomach, the esophagus also must withstandthe entry of air and gastric contents. The bar-rier functions of the esophagus are accom-plished by the presence of sphincters at eachend of the organ.

Anatomically the esophageal muscle is ar-ranged in two layers: an inner layer with themuscle fibers organized in a circular axis andan outer layer with the fibers organized in alongitudinal axis. The UES consists of a thick-ening of the circular muscle and can be iden-tified anatomically as the cricopharyngealmuscle. This muscle, like the musculature of

the proximal third of the esophageal body,is striated. The distal third of the esophagusis composed of smooth muscle; although theterminal 1 to 2 centimeters (cm) of the mus-culature acts as a lower esophageal sphinc-ter (LES), no separate sphincter muscle canbe identified anatomically. The middle thirdof the body of the esophagus is composed ofa mixture of muscle types with a descendingtransition from striated to smooth fibers.

The events that occur in the esophagusbetween and during swallowing are oftenmonitored by placing pressure-sensingdevices at various levels in the esophageallumen. Such devices indicate that betweenswallows, both the UES and the LES areclosed and the body of the esophagus is flac-cid ( Fig. 3-3, A). In the region of the UES,pressure is as much as 60 millimeters of mer-cury (mm Hg) higher than that in thepharynx or body of the esophagus. A zoneof elevated pressure also is found at the LES.The length of this zone may range from sev-

eral millimeters to a few centimeters, andthe pressure may be 20 to 40 mm Hg higherthan on either side. Pressures in the body ofthe esophagus are similar to those within thebody cavity in which the esophagus lies. Inthe thorax the pressures are subatmospher-ic and vary with respiration; they drop withinspiration and rise with expiration. Thesefluctuations in pressure with respiration re-verse below the diaphragm, and intralumin-al esophageal pressure reflects intra-abdom-inal pressure, which is slightly higher thanatmospheric pressure.

FIGURE 3-3 Manometric recordings fromthe esophagus and the orad portion of thestomach. Intraluminal pressures from theupper esophageal sphincter (UES), fourareas of the esophagus, the lower esopha-geal sphincter (LES), and the gastric fundusare shown. A, Between swallows, both theupper and the lower sphincters are closed,as indicated by the greater than atmospher-ic pressures recorded there. Pressures inthe body of the esophagus reflect in-

trathoracic or intra-abdominal pressures.Pressures in the fundus reflect intra-abdom-inal pressure plus tonic contractions of thefundus. B, On swallowing, the upper sphinc-ter relaxes before passage of the bolus.After bolus passage it contracts, followed bya peristaltic contraction in the body of theesophagus. To allow passage of the bolusinto the stomach, the lower sphincter andthe orad stomach relax before the peristalticcontraction reaches them.

During a swallow the sphincters and thebody of the esophagus act in a coordinatedmanner ( Fig. 3-3, B). Shortly before the distalpharyngeal muscles contract, the UES opens.Once the bolus passes, the sphincter closesand assumes its resting tone. The body ofthe esophagus undergoes a peristaltic con-traction.

This contraction begins just below the UESand occurs sequentially at progressivelymore distal segments to give the appearanceof a contractile wave moving toward the

stomach. After the contractile sequencepasses, the esophageal muscle becomes flac-cid again. Shortly before the peristaltic con-traction reaches the LES, the sphincter re-laxes. After passage of the bolus the sphinc-ter contracts back to its resting level. Com-pared with the rapid events in the pharynx,esophageal peristalsis is slow. The peristalticcontraction moves down the esophagus atvelocities ranging from 2 to 6 cm/second,and it may take the bolus 10 seconds to reachthe lower end of the esophagus.

When esophageal peristalsis is precededby a pharyngeal phase, it is called primaryperistalsis. Esophageal contractions,however, can occur in the absence of both or-al and pharyngeal phases. This phenomenonis called secondary peristalsis and is elicitedwhen the esophagus is distended. Secondaryperistalsis occurs if the primary contractionfails to empty the esophagus or when gastriccontents reflux into the esophagus. Initiation

of secondary peristaltic contractions is invol-untary and normally is not sensed.

The effect of esophageal peristalsis on bol-us transport depends on the physical prop-erties of the bolus. If a person in an uprightposition swallows a liquid bolus, it actuallyreaches the stomach several seconds beforethe peristaltic contraction. Thus althoughboth sphincters must relax to allow transportof all materials, esophageal peristalsis is notalways necessary. For most swallowed ma-terial, peristaltic contractions are essentialfor progression to the stomach, and repet-itive secondary contractions are often re-quired to sweep the bolus completely intothe stomach.

Control of esophageal peristalsis is com-plex and not fully understood. Closure of theUES is maintained by the normal elasticity ofthe sphincteric structures and active contrac-tion of the cricopharyngeal muscle. Relaxa-tion of the UES is coordinated with contrac-tion of the pharyngeal musculature. As the

larynx rises during the pharyngeal compon-ent of swallowing, the cricopharyngeal areais displaced. This displacement, along withrelaxation of the cricopharyngeal muscle, al-lows the sphincter to open. Relaxation of thecricopharyngeal muscle is brought about bya suppression of nerve impulses from theswallowing center via the activity of the nuc-leus ambiguus.

Contractions of the body of the esophagusare coordinated by both central and peri-pheral mechanisms. This region of the eso-phagus is innervated primarily by the vagusnerves. These nerves are partly of the somat-ic motor type, arising from the nucleus am-biguus, and partly of the visceral motor type,arising from the dorsal motor nucleus. Thesomatic motor nerves synapse directly withstriated muscle fibers of the esophagus ( Fig.3-4). The visceral motor nerves do not syn-apse directly with the smooth muscle cellsbut rather with nerve cell bodies that liebetween the longitudinal and circular

muscle layers. These local nerves in turn in-nervate the smooth muscle cells, as well ascommunicate with one another along thelength of the esophagus.

FIGURE 3-4 Efferent innervation of thebody of the esophagus. Special visceral so-matic fibers directly innervate the striatedmuscle fibers of the circular and longitudinalmuscle layers. Preganglionic fibers from thevagus innervate the ganglion cells of the in-trinsic plexus. Fibers from the ganglion cellsthen innervate the smooth muscle cells ofboth layers. In addition, the ganglion cellshave neural connections with one another.

Central control of swallowing originateswithin the swallowing center, which sendsa series of sequential impulses to progress-ively more distal segments of the esophagus.This sequential activation results in a peri-staltic contraction. The central nervous sys-tem does not totally control peristalsis,however. In smooth muscle areas of the eso-phagus, peristalsis can occur after bilateralcervical vagotomy (cutting of the vagusnerve). Furthermore, peristalsis can be in-duced in excised esophagi that have beenplaced in an organ bath. In these instances,

peristalsis must be coordinated by the in-trinsic nerve plexuses or the smooth musclecells themselves.

The presence of secondary peristalsis in-dicates the importance of afferent input tothe central and peripheral mechanisms con-trolling swallowing. Afferent input providedby distention of the esophagus not only ini-tiates secondary peristalsis but also affectsthe intensity of contractions. Variation in thesize of the bolus being swallowed leads toa variation in the amplitude of esophagealcontraction. Indeed, afferent stimulation ap-pears so important that a peristaltic se-quence may not occur unless a bolus is swal-lowed and elicits afferent stimulation. Con-versely, intense afferent stimulation, such asthat provided by inflation of a balloon in thebody of the esophagus, can inhibit the pro-gression of peristaltic contractions past theballoon.

Contraction of the LES is regulated by theintrinsic properties of the smooth muscle

fibers, as well as by neural and humoral in-fluences. Smooth muscle from this area ofthe esophagus responds to passive stretch-ing by contracting to oppose the stretch. Thisresponse does not depend on nervous activ-ity. Thus the basic tone of the LES may betotally myogenic. Nevertheless, this tone isunder several neural and humoral influen-ces. For example, resting tone is increased bycholinergic agonists and by the gastrointest-inal hormone gastrin. Sphincteric tone is de-creased by agents such as isoproterenol andprostaglandin E1.

Transient relaxation of the LES duringswallowing is mediated through entericnerves. The enteric inhibitory nerves can beactivated by stimulation of the vagus nerveand by distention of the body of the eso-phagus, thus activating aborad entericnerves. The neurochemical basis for this re-sponse is not known, although roles for bothvasoactive intestinal peptide (VIP) and nitricoxide (NO) have been proposed.

Receptive Relaxation ofthe StomachSwallowing also involves the stomach. Interms of motility functions, the stomach canbe divided into two major areas: the orad por-tion, which consists of the fundus and a por-tion of the body; and the caudad portion,which consists of the distal body and the an-trum ( Fig. 3-5). These two regions havemarkedly different patterns of motility thatare responsible, in part, for two major func-tions: accommodation of ingested materialduring swallowing and regulation of gastricemptying. Accommodation is attributableprimarily to activities of the oral region,whereas both regions are involved in the reg-ulation of gastric emptying (see Chapter 4).

FIGURE 3-5 Divisions of the stomach. Fordiscussions of secretion, the stomach usu-ally is divided into the fundus, body, and an-trum. For discussions of motility, it can bedivided into an orad area and a caudadarea. Shading denotes the approximate ex-tent of the caudad area.

During a swallow, the orad region of thestomach relaxes at about the same time as

the LES. Intraluminal pressures in both re-gions fall before arrival of the swallowedbolus because of active relaxation of thesmooth muscle in both regions (see Fig. 3-3,B). After passage of the bolus, the pressure inthe stomach returns to approximately whatit was before the swallow. This process hasbeen termed receptive relaxation. Becauserelaxation happens with each swallow, largevolumes can be accommodated with a min-imal rise in intragastric pressure. For ex-ample, the human stomach can accept 1600cubic centimeters (cc) of air with a rise inpressure of no more than 10 mm Hg.

Receptive relaxation is mediated by avagovagal reflex, a nervous reflex that has itsafferent and efferent pathways in the vagusnerve. If this nerve is transected, receptiverelaxation is impaired and the stomach be-comes less distensible. Studies indicate thatvagal impulses may act through5-hydroxytryptamine receptors to releaseNO to cause the muscle to relax.

CLINICALAPPLICATIONSContractions of pharyngealmuscle are controlled solely byextrinsic nerves. Therefore cer-tain neurologic diseases (e.g.,cerebrovascular accident) canhave an adverse effect on thisphase of swallowing. Aspirationoften occurs because contrac-tions in the pharynx and upperesophageal sphincter (UES) areno longer coordinated. A similarclinical picture can be seen in dis-eases that affect striated muscleor the myoneural junction.

Diseases affecting the smoothmuscle portion of the esophaguspredictably cause abnormalitiesin peristalsis and in the tone ofthe lower esophageal sphincter(LES). In achalasia, for example,

the LES often fails to relax com-pletely with swallowing. Thismay be coupled with a loss ofperistalsis in the esophagealbody, a complete absence of con-tractions, or the appearance ofsimultaneous rather than se-quential contractions, with res-ulting impaired transit.

Patients with this disorderhave considerable difficultyswallowing, often aspirate re-tained esophageal content, andmay become severely malnour-ished. This disorder has been at-tributed to abnormalities in theenteric nerves. In another disor-der, diffuse esophageal spasm,simultaneous contractions of along duration and high amp-litude can occur. Affected per-sons have difficulty swallowing

and may complain of chest pain.Although not always sympto-matic, abnormalities in the eso-phageal component of swallow-ing can occur as part of a varietyof systemic diseases. Examplesare diabetes mellitus, chronic al-coholism, and scleroderma.

Motor dysfunction also canplay an important contributoryrole in the pathogenesis of otheresophageal diseases. The mostcommon symptom associatedwith esophageal dysfunction isheartburn. This burning sensa-tion is caused by the reflux ofgastric acid into the esophagusand the resulting injury to theesophageal mucosa. This condi-tion may be produced by motorabnormalities that result in ab-normally low pressures in the

LES or by the failure of second-ary peristalsis to empty the eso-phagus effectively. Reflux mayalso occur if intragastric pressureincreases, as may occur follow-ing a large meal, during heavylifting, or during pregnancy. Per-sistent reflux and the resultinginflammation lead to gastroeso-phageal reflux disease (GERD).This condition is usually treatedeffectively with inhibitors ofgastric acid secretion. In somecases a region of the proximalstomach moves through the dia-phragm into the thorax and pro-duces severe gastric reflux. Thiscondition is termed hiatal herniaand is often treated by surgery.Reflux itself is not abnormal, andit occurs several times a day.Under normal conditions the re-

fluxed acid is cleared from theesophagus, and no symptomsdevelop.

CLINICAL TESTSSwallowing is assessed clinicallyby x-ray examination with bari-um and by esophageal mano-metry. In the x-ray study the pa-tient swallows a bolus of liquidbarium sulfate. Because this ma-terial is radiopaque, it can be ob-served fluoroscopically and re-corded on the x-ray film as it tra-verses the esophagus, therebyproviding a qualitative descrip-tion of motor events in both thepharynx and the esophagus.

If a more detailed descriptionof events is required or if motor

disorders such as those just de-scribed are suspected, esopha-geal manometry is often useful.Catheters are passed through thenose or mouth so that their tipslie in various regions of the eso-phagus. Pressures detected bythe catheters then are recordedbetween and during swallowingsmall sips of water. These re-cordings provide a quantitativedescription of events occurringin the sphincters and body of theesophagus.

A useful test for episodes ofacid reflux is 24-hour monitoringof intraesophageal pH. A smallpH probe is inserted nasally andpositioned 5 cm above the loweresophageal sphincter. A smallbattery-powered computer is

used for continuous recordingsof pH.

Summary1. Swallowing is initiated voluntarily, butonce initiated, it proceeds as an involuntaryreflex.2. Swallowing is accomplished by peristalticcontraction of pharyngeal muscles, duringwhich time the UES relaxes. This is followedby peristaltic contraction of the esophagealmusculature, during which time the LES andthe orad region of the stomach relax.3. Peristaltic contraction of the pharyngealmuscles, relaxation of the UES, and peristalticcontraction of the striated muscle of the upperesophagus are regulated by pathways withinthe central nervous system. Peristaltic con-traction of the smooth muscle of the loweresophagus and relaxation of the LES are regu-lated by pathways within the central nervoussystem and by pathways within the intrinsicnerves.

4. Contraction of the pharynx and esophaguscan be initiated by swallowing (primaryperistalsis). Contraction of the esophaguscan be initiated by stimulation of receptorswithin the esophagus (secondary peri-stalsis).5. Tonic contraction of the LES betweenswallows is the result of an interplay of ex-citatory and inhibitory neural and hormonalinfluences acting on an intrinsic myogeniccontraction. During a swallow, intrinsicnerves release a transmitter (perhaps NO orVIP) to cause muscle relaxation.6. Contraction of the orad stomach is the res-ult of an interplay of excitatory and inhib-itory neural and hormonal influences actingon an intrinsic myogenic contraction. Duringa swallow, the orad stomach relaxes (recept-ive relaxation) in response to activation of in-hibitory nerves in the vagus.

KEY WORDS ANDCONCEPTS

Oral ingestionChewing reflexOropharynxTongueOral cavityNasopharynxGlottisLarynxPeristaltic contractionPharynxUpper esophageal sphincterSwallowing centerEsophagusLower esophageal sphincterPrimary peristalsisSecondary peristalsisVagotomyOrad portionCaudad portionReceptive relaxationVasovagal reflexAchalasia

Diffuse esophageal spasmHeartburnGastroesophageal reflux diseaseHiatal hernia

Suggested ReadingsBiancani, P., Harnett, K. M., Behar, J., Esophageal

motor functionYamada, T., Alpers, D. H., Laine,L., et al, eds. Textbook of Gastroenterology, ed 3,vol 1. Philadelphia: Lippincott Williams &Wilkins, 1999.

Mittal, R. K., Motor function of the pharynx, the eso-phagus, and its sphinctersJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol1. San Diego: Elsevier, 2012.

Roman, C., Gonella, J., Extrinsic control of digestivetract motilityJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 2, vol 1. New York:Raven Press, 1987.

Shaker, R., Pharyngeal motor functionJohnson, L. R.,eds. Physiology of the Gastrointestinal Tract, ed 4,vol 1. San Diego: Elsevier, 2006.

Tack, J., Neurophysiologic mechanisms of gastricreservoir functionJohnson, L. R., eds. Physiologyof the Gastrointestinal Tract, ed 5, vol 1. SanDiego: Elsevier, 2012.

Gastric Emptying

Object ives

Describe the contractions of the orad andcaudad regions of the stomach.Explain the regulation of the contractileactivity of the stomach, including the role ofslow waves.List the components of the gastric contentsthat affect the rate of gastric emptying.Understand the role of duodenal receptorsin the regulation of gastric emptying.Describe the changes in motility that regu-late gastric emptying.

Describe the disorders that may result inan impairment of gastric emptying.

Motility of the stomach and upper small in-testine is organized to accomplish the or-derly emptying of contents into the duo-denum in the presence of ingested materialof variable quantity and composition. Ac-commodation and temporary storage of in-gested material result from receptive relax-ation of the orad stomach (see Chapter 3).Emptying, which also requires mixing inges-ted material with gastric juice and reducingthe particle size of any solids that have beenswallowed, results from integrated contrac-tions of the orad stomach, caudad stomach,pylorus, and duodenum.

Anatomic ConsiderationsGastric contractions result from activity ofsmooth muscle cells that are arranged in threelayers: an outer longitudinal layer, a middlecircular layer, and an inner oblique layer. Thelongitudinal layer is absent on the anteriorand posterior surfaces of the stomach. Thecircular layer is the most prominent and ispresent in all areas of the stomach except theparaesophageal region. The oblique layer,the least complete, is formed from two bandsof muscle lying on the anterior and posteriorsurfaces. These two bands meet at the gast-roesophageal sphincter and fan out to fusewith the circular muscle layer in the caudadpart of the stomach. Both the circular and thelongitudinal muscle layers increase in thick-ness toward the duodenum.

The stomach is richly innervated with bothintrinsic and extrinsic nerves. The intrinsicnerves lie in various plexuses, the most prom-

inent being the myenteric plexus, which liesin a three-dimensional matrix between thelongitudinal and circular muscle layers andthroughout the circular muscle layer. Themyenteric plexus receives nerve endingsfrom other intrinsic plexuses, as well as fromextrinsic nerves. Axons from neurons withinthe myenteric plexus synapse with themuscle fibers and with glandular cells of thestomach. Extrinsically the stomach is innerv-ated by branches of the vagus nerves and byfibers originating in the celiac plexus of thesympathetic nervous system.

The pylorus, or gastroduodenal junction,is characterized by a thickening of the cir-cular muscle layer of the distal antrum. Se-parating this bundle of muscle from the duo-denum is a connective tissue septum;however, some of the longitudinal musclefibers pass from the antrum to connect withmuscle cells of the duodenum. The pylorusis richly innervated with both extrinsic andintrinsic nerves, and nerve endings within

the thickened circular muscle layer areabundant. Many of these endings containneuropeptides, especially enkephalin, andmany produce and release nitric oxide (NO).

The anatomy of the proximal duodenumis similar to that of the rest of the intestine(described in Chapter 5). A significant differ-ence is the larger number of intrinsic nervespresent in this area compared with the restof the small bowel. These nerves may be in-volved in the regulation of gastric emptying(described in a later section).

In addition to the muscle cells and nerves,interstitial cells of Cajal (ICCs) also areprominent in all regions and appear to play aprominent role in regulating motility. ManyICCs form gap junctions with smoothmuscle cells, whereas others appear to createa bridge between nerve endings and smoothmuscle cells.

Contractions of the OradRegion of the StomachAs detailed in the previous chapter, the pre-dominant motor activity of the orad region ofthe stomach is the accommodation of ingestedmaterial. The musculature of the orad stom-ach is thin, contractions are weak, and dur-ing the remainder of the digestive state, pres-sures are essentially equal to intra-abdominalpressure, with superimposed tonic pressurechanges. These pressure changes are predom-inantly of low amplitude and have durationsof 1 minute or more. The contractions thatproduce these pressure changes reduce thesize of the stomach as the stomach empties.These tonic contractions result in accommod-ation of the remaining gastric contents andpropulsion of those contents into the caudadstomach. A consequence of this minimal con-tractile activity is that little mixing of ingested

contents occurs in the orad stomach. Con-tents often remain in relatively undisturbedlayers for an hour or more after eating. Asa result, salivary amylase (see Chapter 7),which is inactivated by gastric acid, can di-gest a significant portion of the starchpresent in a meal. Little is known about theregulation of contractions in the orad stom-ach during digestion. Both gastrin andcholecystokinin (CCK) decrease contractionsand increase gastric distensibility. However,only the effect of CCK appears to bephysiologic.

Contractions of theCaudad Region of theStomachIn the fasted state, the stomach is mostly qui-escent. After eating, phasic contractions ofvariable intensity occur almost continuously.Contractions normally begin in the midstom-ach and move toward the gastroduodenaljunction ( Fig. 4-1). Thus the primary contract-ile event is a peristaltic contraction. As con-tractions approach the gastroduodenal junc-tion, they increase in both force and velocity.At any one locus of the human stomach, theduration of each contraction ranges between 2and 20 seconds, and the maximum frequencyis approximately three contractions perminute. Between contractions, pressures inthe caudad region are near intra-abdominallevels.

FIGURE 4-1 Intraluminal pressures recor-ded from five areas of the stomach. Asensor in the orad region records littlephasic activity. Sensors in the caudad re-gion detect peristaltic contractions, whichbegin in the midportion of the stomach andprogress toward the gastroduodenal junc-tion. The contractions increase in force andvelocity as they near the junction, and theyrepeat at multiple intervals of 12 to 20seconds. The presence and force of con-tractions depend on the digestive state ofthe individual.

Contractions of the caudad region of thestomach serve to both mix and propel gastriccontents. Once a contraction begins in themidportion of the stomach, gastric contentsare propelled toward the gastroduodenaljunction ( Fig. 4-2, A). As the contraction ap-proaches the gastroduodenal junction, somecontents are evacuated into the duodenum (Fig. 4-2, B). However, because the peristalt-ic wave increases in velocity as it approachesthe junction, the contraction overtakes thegastric contents. Once this occurs, most ofthe contents are propelled back into the mainbody of the stomach ( Fig. 4-2, C), where theyremain until the next contraction sequence( Fig. 4-2, D). This propulsion back into thestomach has been termed retropulsion. Ret-ropulsion causes a thorough mixing of thegastric contents and mechanically reducesthe size of solid particles. (See videos: ht-tp://www.wzw.tum.de/humanbiology/motvid01/movie_11_1mot01.wmv; ht-tp://www.wzw.tum.de/humanbiology/

motvid01/movie_13_1mot01.wmv; accessedMarch 2013).

FIGURE 4-2 Effects of gastric peristalticcontractions on intraluminal contents. A,The contraction begins in the midregion ofthe stomach and pushes contents towardthe duodenum. B, As the contraction in-creases in force and velocity, some of thecontents are passed over and are forcedback into the body of the stomach. C, Con-traction force and velocity are great enoughto cause rapid and almost complete closureof the distal antrum. Before and during this

contraction, a portion of the contents is pro-pelled into the duodenum. However, most ispropelled back into the body of the stomach.D, No gross movement of the gastric con-tents occurs between contractions.

Contractions of the caudad area of thestomach are controlled by interactionsamong smooth muscle cells and ICCs, aswell as by nervous and humoral elements.Smooth muscle cells in this area have a mem-brane potential that fluctuates rhythmicallywith cyclic depolarizations and repolariza-tions. These fluctuations are called slowwaves (also referred to as basic electricrhythm, pacesetter potentials, and control activ-ity). Slow waves have two components: aninitial upstroke potential and a secondaryplateau potential. In the stomach, slowwaves can initiate significant contractions;thus some investigators refer to them as ac-tion potentials. However, slow waves are al-ways present, regardless of the presence or

absence of contractions. Their frequency isconstant, and humans have approximately 3cycles/minute (cpm). When slow waves arerecorded from multiple sites between themidstomach and the gastroduodenal junc-tion, they have the same frequency at all sites( Fig. 4-3). However, slow waves do not oc-cur simultaneously at all points along thestomach. Rather, a phase lag occurs; thus,they seem to pass from an area in the mid-stomach toward the gastroduodenal junc-tion. This phase lag between slow waves atequidistant points lessens as the gastroduo-denal junction is neared. The frequency andvelocity of the peristaltic waves are thereforecontrolled by the frequency and velocity ofspread of the slow wave.

FIGURE 4-3 Electrical activity of smoothmuscle cells of the stomach. Electrodesplaced on the serosal surface record nochanges from the orad region. In the midre-gion, however, slow waves occur continu-ously at intervals of 12 to 20 seconds. Slowwaves give the appearance of movingthrough the caudad region at increasing ve-locities. Compare this with Figure 4-1. mV,microvolts. (Adapted from Kelly KA, Code CF, Elve-

back LR: Patterns of canine gastric electrical activity. Am J

Physiol 217:461-471, 1969.)

Nervous and humoral factors are not ne-cessary for the presence of slow waves, but

they do alter slow wave behavior. Vagotomydisorganizes the slow waves so that thephase lag varies in both duration and direc-tion. The hormone gastrin increases the fre-quency of gastric slow waves, although ithas little effect on the apparent propagationof the waves through the musculature.

Simultaneous recordings of both electricaland mechanical activities have shown thatslow waves initiate significant contractionsof the musculature only when the plateaupotential exceeds a threshold ( Fig. 4-4).Once the threshold is exceeded, the greaterthe amplitude of the plateau, the greater willbe the force of contraction. The plateau po-tential may or may not be accompanied bysuperimposed rapid oscillations called spikepotentials or spike bursts. These oscillationsalso appear to initiate contractions and areseen more frequently in muscle of thecaudad antrum. Threshold values for con-traction are not reached by every slow wave.Therefore not every slow wave is accompan-

ied by a contraction. If the threshold isreached, it is only during a specific phase ofthe slow wave cycle. Thus the phasic andperistaltic nature of gastric contractions res-ults from the presence of slow waves.

FIGURE 4-4 A, Relationship betweenelectrical and mechanical activities ofsmooth muscle from the caudad region ofthe stomach. Bottom tracing depicts twoslow waves (action potentials) superim-posed. Top tracing depicts mechanicalevents associated with the potentialchanges. Note that a contraction is initiated

only by the slow wave of larger amplitudeand longer duration. B, Slow wave potentialrecorded from distal antrum. Note the oscil-lations and spike potentials during plateau.(A, Adapted from Szurszewski JH: Mechanism of action of

pentagastrin and acetylcholine on the longitudinal muscle

of the canine antrum. J Physiol 252:335-361, 1975; B, Ad-

apted from El-Sharkaway TY, Morgan KG, Szurszewski

JH: Intracellular electrical activity of canine and human

gastric smooth muscle. J Physiol 279:291-307, 1978.)

Whether an individual slow wave resultsin a contraction and the amplitude of con-tractions are determined by hormonal andneural activity, which in turn depends onthe digestive state of the individual and thenature of the gastric contents. These eventsregulate not only the level of the plateau ofthe slow wave but also the amount of spik-ing and therefore both the frequency andstrength of contractions. Vagal nerve tran-section leads to a decrease in contractions,whereas vagal stimulation increases thenumber and force of contractions. Usually,

sympathetic nerve activity depresses con-tractions. Gastrin and motilin increase con-tractions, whereas secretin and gastric inhib-itory peptide (GIP) inhibit them. Thephysiologic significance of the gastric motoreffects of secretin and GIP is doubtful.

Contractions of theGastroduodenal JunctionThe question whether a true sphincter existsbetween the stomach and the duodenum isunsettled. There is a definite difference in thecontractile activities of the stomach, on oneside, and of the duodenum, on the other. Onecontracts at a frequency of approximately 3cpm, and the other contracts at approximately12 cpm. The thickened ring of circular musclebetween the two organs appears to behave in-dependently. In humans, some investigatorshave demonstrated a zone of elevated pres-sure between the stomach and the duodenum(an indication of sphincteric activity); otherinvestigators, however, have not found suchan area. Studies show that even if a zone of el-evated pressure is not found, the pylorus cancontract independently, thus altering the res-istance to flow between the stomach and duo-

denum ( Fig. 4-5). This action can have alarge effect on gastric emptying.

FIGURE 4-5 Intraluminal pressures recor-ded from two areas of the stomach (an-trum), the pylorus, and two areas of theproximal duodenum during the intraduo-denal infusion of lipid. Note the regular isol-ated contractions, and the elevated pres-sures (0 indicates atmospheric pressure ineach tracing) between contractions, in thepylorus. This activity is occurring at a timewhen no contractions are present in thestomach and duodenum. (Adapted from Heddle R,

Dent J, Read NW, et al: Antropyloroduodenal motor re-

sponses to intraduodenal lipid infusion in healthy volun-

teers. Am J Physiol 254:G671-G679, 1988.)

Contractions of theProximal DuodenumDuodenal contractions are mostly phasic. Al-though their maximum frequency can be ap-proximately 12 per minute in the digestivestate, these contractions seldom occur in acontinuous manner. Rather, single, isolatedcontractions, or small groups of contractions,separated by intervals of no contractions, arethe norm. In addition, duodenal contractionsare not always peristaltic. Most contractionsof the small intestine are of the segmentingtype (see Chapter 5). Thus depending on theirnumber and pattern, duodenal contractionseither impede or facilitate the emptying ofcontents from the stomach.

Regulation of GastricEmptyingImmediately after ingestion of a meal, thestomach may contain more than a liter of ma-terial, which takes several hours to leave thestomach and empty into the small intestine.Gastric emptying is accomplished by coordin-ated contractile activity of the stomach, pylor-us, and proximal small intestine ( Fig. 4-6).Emptying appears to be regulated in a man-ner that allows for optimal intestinal diges-tion and absorption of foodstuffs ( Fig. 4-7).Solids empty only after a lag period duringwhich they are reduced in size by retropuls-ive activity of the caudad stomach. Onlyparticles approximately 1 mm3 or smaller arereadily emptied during the digestive phaseof gastric motility. Conversely, liquids beginto empty almost immediately. The rate ofemptying of both solids and liquids depends

on their chemical compositions. Materialsthat are high in lipids or hydrogen (H+) orthat deviate markedly from isotonicity allempty at a slower rate than that observed fornear-isotonic saline solutions.

FIGURE 4-6 Regulation of gastric empty-ing. A, Hypothetic conditions immediatelyafter the rapid ingestion of a meal and be-fore the onset of any contractile activity.This outline is superimposed in B and C toillustrate changes. B, Conditions favoringemptying are increased tone of the orad re-gion of the stomach, forceful peristaltic con-tractions of the caudad region of the stom-ach, relaxation of the pylorus, and absenceof segmenting contractions of the duo-denum. As nutrients emptied from the stom-ach are further digested and absorbed inthe small intestine, they excite receptorslocated in the intestinal mucosa. Activationof these receptors results in C. C, Relaxa-tion of the orad region of the stomach, a de-

crease in the number and force of contrac-tions of the caudad region of the stomach,contraction of the pylorus, and an increasein segmenting contractions of the duo-denum. These actions result in a slowing ofgastric emptying.

FIGURE 4-7 Solid and liquid componentsof a meal were labeled so that their empty-ing from the stomach could be followed overtime after ingestion of the meal. As indic-ated by the sharp decrease in the fractionremaining in the stomach, the liquid com-ponent began to empty almost immediately,

and it also emptied more rapidly. Con-versely, there was a lag time before theemptying of the label attached to the solidcomponent, and this label emptied moreslowly. The reason for this slower emptyingwas that the solid component had to be re-duced to small particles before being emp-tied into the duodenum. (Adapted from Camilleri M,

Malagelada JR, Brown ML, et al: Relation between antral

motility and gastric emptying of solids and liquids in hu-

mans. Am J Physiol 249:G580-G585, 1985.)

Changes in gastric emptying are causedby alterations in the motility of the stomach,gastroduodenal junction, and duodenum.Decreases in distensibility of the orad stom-ach, increases in the force of peristaltic con-tractions of the caudad stomach, and in-creases in the diameter and inhibition of seg-menting contractions of the proximal duo-denum all lead to an increased rate of gastricemptying. Inhibition of emptying occurs onreversal of one or more of these contractileactivities (see Fig. 4-6).

Regulation of emptying results from thepresence of receptors that lie in the uppersmall bowel. These receptors respond to thephysical properties (e.g., osmotic pressure)and chemical composition (e.g., H+, lipids)of the intestinal contents. As contents emptyfrom the stomach, intestinal receptors loc-ated in the duodenum are activated. Recept-or activation triggers several neural and hor-monal mechanisms that inhibit gastricemptying. For example, fats release CCK,which increases the distensibility of the oradstomach. Acid, when placed in the duo-denum, inhibits motility and emptying witha latent period as short as 20 to 40 seconds,a finding indicating that the inhibition is theresult of neural reflex. This reflex appears tobe entirely intrinsic, with information fromthe duodenal receptors to the gastric smoothmuscle carried by neurons of the intramuralplexus. Other hormones such as secretin andGIP also inhibit emptying but do not appearto do so in physiologic concentrations. Neur-

al input that activates the sympathetic sys-tem, such as that produced by pain, anxiety,fear, or even exercise, may slow gastricemptying. Much of the regulation of gastricemptying is mediated by as yet undefinedpathways, but it is obvious that regulationallows time for osmotic equilibration, acidneutralization, and solubilization and diges-tion of lipids.

The pattern of motility of the gastroduo-denal area changes after the nutrient com-ponents of the meal have been digested andabsorbed. Any large particles of undigestedresidue that remain in the stomach are emp-tied by a burst of peristaltic contractions(phase 3) as part of the migrating motor com-plex (MMC) ( Fig. 4-8). During this shortburst, powerful contractions begin in thepreviously inactive orad region and sweepthe entire length of the stomach. The pylorusdilates and the duodenum relaxes duringeach sweep so that the resistance to empty-ing is minimal. Then duodenal contractions

sweep the contents onward (see Chapter 5).(See video: http://www.wzw.tum.de/hu-manbiology/motvid02/movie_06_1mot02.wmv; accessed March2013). After a burst of activity, the regionremains relaxed for an hour or more. Thenintermittent contractions begin and lead toanother burst. This cycle repeats every 90minutes or so until ingestion of the nextmeal. Premature bursts can be initiated byinjection of the hormone motilin and bydrugs (e.g., erythromycin) thought to act onmotilin receptors.

FIGURE 4-8 Schematic of intraluminalpressures recorded from the stomach andproximal duodenum during an active phaseof a migrating motor complex. Phasic con-tractions begin in the orad region of thestomach and propagate over the caudad re-gion. As contractions of the caudad regionapproach the gastroduodenal junction, thepylorus relaxes (not shown) and duodenalcontractions are momentarily inhibited. Thisprocess allows contents to be swept into theduodenum. Contents are then propelled to-ward the colon, as described in Chapter 5.(Adapted from Malagelada JR, Azpiroz F: Determinants of

gastric emptying and transit in the small intestine. In

Schultz SG, Wood JD, Rauner BB [eds]: The Gastrointest-

inal System, vol 1. Bethesda, MD, American Physiological

Society, 1989.)

CLINICALAPPLICATIONSDisorders of gastric motility gen-erally are manifested by a rateof gastric emptying that is eithertoo slow or too fast. This condi-tion may reflect an abnormalityin one or all of the major motorfunctions of the stomach. Whenthe stomach fails to empty prop-erly, the affected person exper-iences nausea, loss of appetite,and early satiety, and gastriccontents often may be vomited.The most common cause of im-paired emptying is obstruction atthe gastric outlet. Examples of

disorders that may result in ob-struction are gastric cancer andpeptic ulcer disease. In the latter,the gastric lumen at the pylorusmay actually become occludedfrom inflammation and scarringassociated with the ulcer. Im-paired emptying also can becaused by the absence or disor-ganization of motor events in thecaudad stomach. These phenom-ena occur with a variety of meta-bolic disorders, such as diabetesmellitus and potassium deple-tion.

Vagus nerve section (vago-tomy) invariably leads to a delayin gastric emptying of solids.Consequently, vagotomy (e.g.,performed to decrease acid se-cretion in peptic ulcer disease) iscoupled with surgical alterations

of the pylorus (pyloroplasty) orcreation of a new gastric outlet(gastroenterostomy) in an at-tempt to avoid this complication.After such an operation, empty-ing of liquids generally is accel-erated, but even with alterationof the gastric outlet, emptying ofsolids still may be slowed. Mostpatients undergoing this type ofsurgical procedure experience noother symptoms. However, somemay experience diarrhea, sweat-ing, palpitations, cramps, and avariety of other unpleasantsymptoms, which may be theresult of rapid emptying thatconstitutes dumping syndrome.This in turn causes the rapidentry of large volumes of fluidinto the upper small bowel to

bring the hypertonic contents toisotonicity.

It is speculated that motilityabnormalities may underlie orcontribute to other diseases ofthe upper gastrointestinal tract.For example, gastric emptying isaccelerated in patients with aduodenal ulcer. This acceleratedemptying may enhance the de-livery of gastric acid to the duo-denum and perhaps may over-whelm the ability of the duo-denal mucosa to defend itselfagainst injury. Alternatively, forpatients with a gastric ulcer,gastric emptying appears to beslowed. This slowing may renderthe stomach more susceptible toinjury.

CLINICAL TESTSA qualitative assessment of gast-ric motility and emptying can beobtained by x-ray and fluoro-scopic evaluation of a barium-filled stomach. Aspiration of thestomach at specific intervals afterinstillation of an isotonic salinesolution also gives informationon gastric emptying. A morequantitative test involves gammascintigraphy. For this test, ra-diolabeled liquid or solid food,or both, is ingested, and gammacameras are used to scan thestomach at various times after-ward. The fraction of material re-maining in the stomach is thenplotted as a function of time (seeFig. 4-7). In certain laboratories,manometry similar to that usedin assessing esophageal motility

can be employed. Compliance ofthe orad stomach can be assessedusing a “barostat,” a large bagplaced in the stomach that mon-itors changes in volume underset pressures. More recently,magnetic resonance imaging andultrasonography have been em-ployed as noninvasive methodsto assess gastric motility andemptying.

Summary1. Contractile activity of the orad stomachvaries with the digestive state. After the oradregion has accommodated a meal, it exhibitslow-amplitude, long-lasting contractions asthe meal empties. After the meal has been di-gested and absorbed, the orad stomach un-dergoes periodic bursts of high-amplitudecontractions as part of the MMC.2. Contractions of the caudad stomach aremostly peristaltic, beginning in the midstom-ach and progressing toward the duodenum.During emptying of a meal, contractions areof variable amplitude and are more or lesscontinuous at a frequency of approximately 3cpm. During the interdigestive period, force-ful peristaltic contractions are grouped intoperiodic bursts as part of the MMC.3. Gastric emptying is highly regulated andinvolves feedback inhibition from receptorslocated in the upper small intestine. Receptors

are stimulated by osmotic pressure, H+, andfatty acids. Stimulation results in patterns ofmotility that slow emptying: decreased toniccontraction of the orad stomach, decreasedforce and number of contractions of thecaudad stomach, increased tone and phasiccontractions of the pylorus, and increasedsegmenting contractions of the upper duo-denum.4. Rhythmic membrane depolarizations andrepolarizations called slow waves occur insmooth muscle cells of the caudad stomach.These waves are omnipresent, occurring ata frequency of approximately three perminute. Each depolarization appears to beinitiated first in the midstomach and then topropagate toward the pylorus. Slow wavesappear to set the timing and the peristalticnature of contractions; however, not everyslow wave initiates a contraction. Those thatdo are of large amplitude and may exhibitsuperimposed spike potentials.

5. Vagotomy results in a decrease in thenumber and force of contractions of thecaudad stomach and a decrease in gastricemptying of solids. Motilin induces contrac-tions that are part of the gastric phase of theMMC.

KEY WORDS ANDCONCEPTSLongitudinal layerCircular layerOblique layerPylorusPeristaltic contractionRetropulsionSlow wavesSpike potentials/spike burstsIntestinal receptorsDuodenal contractionsVagotomyPyloroplastyGastroenterostomyDumping syndrome

Suggested ReadingsEhrlein, H. J., Akkermans, L. M. A. Gastric emptying.

In: Akkermans L. M. A., Johnson A. G., Read N.W., eds. Gastric and Gastroduodenal Motility. NewYork: Praeger, 1984.

Hasler, W. L., The physiology of gastric motility andgastric emptyingYamada, T., Alpers, D. H., Laine,L., et al, eds. Textbook of Gastroenterology, ed 3,vol 1. Philadelphia: Lippincott Williams &Wilkins, 1999.

Hunt, J. N., Knox, M. T., Regulation of gastric empty-ingCode, C. F., eds. Handbook of Physiology, vol4. Baltimore: Williams & Wilkins, 1968.

Rayner, C. K., Hebbard, G. S., Horowitz, M.,Physiology of the antral pump and gastric empty-ingJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 1. San Diego: El-sevier, 2012.

Motility of the SmallIntestine

Object ives

Compare the motility patterns of the smallintestine during feeding and fasting.Describe the functions of slow waves andspike potentials in regulating contractions ofthe small intestine.Describe the functions and control of themigrating motility complex.Explain the peristaltic reflex and theintestino-intestinal reflex.

Describe the motility changes that result invomiting, and discuss the primary factorscontrolling it.

Motility of the small intestine is organized tooptimize the processes of digestion and ab-sorption of nutrients and the aboral propul-sion of undigested material. Thus contrac-tions perform at least three functions: (1)mixing of ingested foodstuffs with digestivesecretions and enzymes, (2) circulation of allintestinal contents to facilitate contact withthe intestinal mucosa, and (3) net propulsionof the intestinal contents in an aboral direc-tion.

Anatomic ConsiderationsContractions of the small intestine are effec-ted by the activities of two layers of smoothmuscle cells: an outer layer with the long axisof the cells arranged longitudinally and an in-ner layer with the long axis of the cells ar-ranged circularly. In general, the circularmuscle layer is thicker, and both layers aremore abundant in the proximal intestine; theydecrease in thickness distally to the level ofthe ileocecal junction.

The small intestine is richly innervated byelements of the autonomic nervous system.Within the wall of the intestine itself lie neur-ons, nerve endings, and receptors of the en-teric nervous system. These neural elementstend to be concentrated in several plexuses.The most prominent, the myenteric orAuerbach plexus, lies between the circularand longitudinal layers of smooth musclecells. Plexal neurons receive input from other

neurons within the plexus, from receptorslocated in the mucosa and muscle walls, andfrom the central nervous system by way ofthe parasympathetic and sympathetic nervetrunks. Plexal neurons provide integratedoutput to smooth muscle cells of both musclelayers, to epithelial cells, and perhaps to en-docrine and immune cells. Many neuro-transmitters are present in the entericnervous system, including acetylcholine,norepinephrine, vasoactive intestinal pep-tide, enkephalin, and other peptides. Fur-thermore, many nerves express nitric oxidesynthase activity.

Interstitial cells of Cajal (ICCs) also areprominent in and adjacent to the entericnerves and muscular layers of the intestine.At least two major classes of ICCs have beenidentified: those responsible for generatingslow waves and those involved in mediatingneural input to the smooth muscle cells.

Extrinsic innervation is supplied by thevagus nerve and by nerve fibers from the

celiac and superior mesenteric ganglia (seeFig. 2-1). Many of the fibers within the vagusare preganglionic, whereas many from theabdominal ganglia are postganglionic. Someof the fibers within the vagus are cholinergic,whereas some from the abdominal plexusesare adrenergic. In addition, nerves that con-tain somatostatin, substance P, cholecys-tokinin (CCK), enkephalin, neuropeptide Y,and other transmitters have been identifiedin afferent and efferent vagal and splanchnicnerves. The exact pathways and physiologicroles of these nerves are being elucidated.

Types of ContractionsBetween contractions, pressures within thelumen of the small intestine approximatelyequal the intra-abdominal pressure. When themusculature contracts, the lumen is occludedpartially or totally, and the pressure increases.Most contractions are local events and in-volve only 1 to 4 centimeters (cm) of bowelat a time. The contractions usually produceintraluminal pressure waves that appear asnearly symmetric peaks of uniform shape (Fig. 5-1). In the human upper small bowel,contractions occur at any one site at multipleintervals of 5 seconds ( Fig. 5-2).

FIGURE 5-1 Intraluminal pressurechanges recorded from the duodenum of aconscious human. Sensors placed 1 cmapart record changes in pressure that arephasic, lasting 4 to 5 seconds. Note that arather large contraction can take place atone site while nothing is recorded 1 cmaway on either side.

FIGURE 5-2 Frequency distribution of7572 contractions recorded at one site inthe human small intestine. Note that thecontractions are most frequent at multiplesof 5 seconds, the approximate intervalbetween slow waves in this region. (From

Christensen J, Glover JR., Macagno EO, et al: Statistics of

contractions at a point in the human duodenum. Am J

Physiol 221:1818-1823, 1971.)

Occasionally other types of pressurewaves can be recorded. One such type con-sists of an elevated baseline pressure that

lasts from 10 seconds to 8 minutes. Thiswave seldom occurs alone and is usually ac-companied by superimposed phasic changesin pressure.

The effect of any contraction on the in-testinal contents depends on the state of themusculature above and below the point ofthe contraction. If a contraction is not co-ordinated with activity above and below, in-testinal contents are displaced both proxim-ally and distally during the contraction andmay flow back during the period of relaxa-tion. This serves to mix and locally circulatethe contents ( Fig. 5-3, A). Such contractionsappear to divide the bowel into segments,and this feature accounts for the name givento this process—segmentation. If, however,the contractions at adjacent sites occur in aproximal-to-distal sequence, aboral propul-sion will result. (See video: ht-tp://www.wzw.tum.de/humanbiology/motvid01/movie_65_1mot01.wmv; accessedMarch 2013).

FIGURE 5-3 The influence of contractionson contents within a region of intestine.Each panel depicts the region at three con-secutive points in time. A, A contraction that

is neither preceded nor followed by othercontractions serves to mix and locally circu-late the intestinal contents. B, Contractionsthat have an orad-to-caudad (left-to-right)sequence serve to propel contents in a netaboral direction.

The small intestine is also capable of elicit-ing a highly coordinated contractile responsethat is propulsive in function. When an areaof bowel is stimulated (e.g., by placement ofa solid bolus of material in the lumen), thebowel responds with contraction orad andrelaxation aborad to the point of stimulation.These events tend to move the material inan aboral direction ( Fig. 5-3, B), and if theyoccur sequentially they can propel a bolusthe entire length of the gut in a short time.This peristaltic response, first described byBayliss and Starling, is known as the law ofthe intestines. Often it is invoked to explainhow material is normally propelled throughthe small bowel. However, peristalsis in-

volving long segments of intestine is seldomseen in normal persons, although peristalticcontractions involving short segments (1 to 4cm) of intestine have been described.

Patterns of ContractionsNot only are there differences in individualcontractions of the intestine, but there alsoare different patterns of contractions. In fast-ing humans, contractions do not occur evenlyover time. Rather, at each locus cycles consist-ing of phases of no or few contractions arefollowed by a phase of intense contractions(phase 3) that ends abruptly ( Fig. 5-4). Theduration of each cycle is the same at adjacentloci of the bowel; however, the 5- to 10-minutephase of intense contractions does not occursimultaneously at all loci. Instead, this phaseappears to migrate aborally, and it takes ap-proximately 1.5 hours to sweep from the duo-denum through the ileum. The characteristicsof this pattern have earned it the title of mi-grating motor complex (MMC). This complexactually begins in the stomach (see Chapter4). (See videos: http://www.wzw.tum.de/hu-manbiology/motvid02/

movie_06_1mot02.wmv; ht-tp://www.wzw.tum.de/humanbiology/motvid02/movie_08_1mot02.wmv; accessedMarch 2013). Its functions appear to be tosweep undigested contents from the stom-ach, through the small intestine, and into thecolon and to maintain low bacterial counts inthe upper intestine. MMCs cycle at intervalsof approximately every 1.5 hours ( Fig. 5-5)as long as the person is fasting.

FIGURE 5-4 Contractions at three loci inthe small bowel. Note that at each locus,phases of no or intermittent contractions arefollowed by a phase of continuous contrac-tions that ends abruptly. Also note that thephase of continuous contractions appears tomigrate aborally along the bowel. Such apattern is called the migrating motor com-plex. (From Rees WD, Malagelada JR, Miller H: Human

interdigestive and postprandial gastrointestinal motor and

gastrointestinal hormone patterns. Dig Dis Sci 27:321-329,

1982.)

FIGURE 5-5 Graphic presentation of thenumber of contractions at three loci in thesmall bowel. The number of contractionsduring each minute of the recording wascounted and plotted against the time of re-cording. The resulting histogram indicatescycles of activity at each locus. Note thatmigrating motor complexes recur at eachlocus at intervals of approximately 100minutes and that the phases of intense con-tractions appear to migrate aborally. (From

Vantrappen G, Janssens J: The interdigestive motor com-

plex of normal subjects and patients with bacterial over-

growth of the small intestine. J Clin Invest 59:1158-1166,

1977.)

In nonfasting persons, the MMC disap-pears, and contractions are spread more uni-formly over time. In the human upper smallbowel, contractions at any one site arepresent 14% to 34% of the recorded time.The most common pattern consists of oneto three sequential contractions separated byperiods of 5, 10, 15, or 20 seconds. These con-tractions are of variable intensity, with noneas forceful as the intense contractions thatoccur during the MMC.

Contractions of the intestine are controlledby activities of the ICCs and smooth musclecells, as well as by nerves and humoral sub-stances. As in the stomach, smooth musclecells in the small intestine have a membranepotential that fluctuates rhythmically withcyclic depolarizations and repolarizations of

5 to 15 millivolts (mV) ( Fig. 5-6). This slowwave activity (or basic electrical rhythm) isalways present whether contractions are oc-curring or not. At any one site in the intest-ine, slow wave frequency is constant. Fre-quency, however, is not the same at all levelsof the bowel. There is a decrease in fre-quency toward the ileocecal junction. In hu-mans the frequency decreases from a meanof approximately 12 cycles/minute (cpm) inthe duodenum to a mean of approximately8 cpm in the terminal ileum. The decreaseis not linear because frequency is constantthroughout the duodenum and for approx-imately 10 cm into the jejunum. Beyond thatpoint, frequency declines more or less lin-early.

FIGURE 5-6 Slow waves and spike poten-tials from multiple sites in the small intest-ine. Tracings 1 to 6 illustrate activity fromprogressively distal areas. The solid lineconnecting the slow waves in tracings 1 to 4denotes the apparent propagation in the re-gion of a slow wave frequency plateau. Tra-cings 5 and 6 show decreases in slow wavefrequency at more distal areas. The rapid

transients that occur on the peaks of someof the slow waves represent spike poten-tials.

Although slow wave frequency is thesame over the proximal small intestine, slowwaves do not occur simultaneously at allpoints. Multiple electrodes detect aproximal-to-distal phase lag that simulates apropagated signal (see Fig. 5-6).

Unlike in the stomach, slow waves them-selves do not initiate contractions in thesmall intestine. Contractions are initiated bya second electrical event, often referred to asspike potential activity. Spike potentials arerapid depolarizations of the smooth musclecell membrane that occur only during thedepolarization phase of the slow wave. Be-cause spike potentials are restricted to onlyone phase of the slow wave cycle, the con-tractions they initiate are phasic. The musclerelaxes during the repolarization phase ofthe slow wave cycle.

During periods when every slow wave isaccompanied by spike potentials, the intest-ine at any site contracts at the same fre-quency as the slow wave frequency at thatsite. Thus slow wave frequency sets the max-imum frequency of contractions at any onesite. In addition, because a gradient existsin the slow wave frequency along the smallbowel, there is a gradient in the maximal fre-quency of contractions. For most of the time,however, spike potentials do not accompanyevery slow wave. During these periods, con-tractions at any one site occur at multiples ofthe slow wave interval. Thus it is no coincid-ence that in the human proximal bowel, slowwaves occur every 5 seconds and contrac-tions occur at multiple intervals of 5 seconds.

Although slow waves at adjacent sitesalong the bowel are always present and aretemporally related, the occurrence of spikepotentials is often localized. Thus sites 1 to 2cm on either side of an area exhibiting slowwaves with spike potentials may exhibit

slow waves only. When this is the situation,segmenting contractions occur. Conversely,when the occurrence of spike potentials isnot localized, slow waves do influence thespatial relationships of contractions at ad-jacent sites. The phase lag in occurrence ofslow waves at adjacent sites imposes a phaselag in the occurrence of contractions at adja-cent sites.

As explained previously, not every slowwave is accompanied by spike potentialsand muscle contraction. The occurrence ofspike potentials and contractions is regu-lated by nervous activity and by circulatingand locally released chemical agents. Certainreflexes depend on the intrinsic neurons, theextrinsic neurons, or both. The peristaltic re-flex (law of the intestines) described previ-ously depends on an intact enteric nervoussystem. Application of neural blockingagents abolishes or greatly reduces this re-flex. Another reflex, the intestino-intestinalreflex, depends on extrinsic neural connec-

tions. If an area of the bowel is grossly dis-tended, contractile activity in the rest of thebowel is inhibited. Sectioning of the extrinsicnerves abolishes this reflex. Additionally, itis well known that changes in emotionalstate can induce alterations in small bowelmotility. Thus the small bowel is under theinfluence of higher centers of the nervoussystem.

In addition to neural control, many cir-culating and endogenously released chemic-als alter intestinal motility. Epinephrine re-leased from the adrenal glands tends to in-hibit contractions. Serotonin, which is con-tained in large quantities within the small in-testine, stimulates contractions, as do certainof the prostaglandins.

Several hormones also alter intestinalmotility. Gastrin, CCK, motilin, and insulintend to stimulate contractions, whereas se-cretin and glucagon tend to inhibit them.The exact role of these chemical agents in theregulation of motility is yet to be clarified.

The presence of a characteristic pattern ofcontractions during fasting—theMMC—indicates complex controlling mech-anisms. The hormone motilin may be in-volved in regulating MMC cycle length.Plasma levels of motilin fluctuate with thesame periodicity as for the phase of intenseduodenal contractions, and exogenously ad-ministered motilin initiates a prematureMMC. Enteric nerves also are involved be-cause their disruption alters MMC initiationand migration. Extrinsic nerves do not seemto be required. Segments of intestine thathave been extrinsically denervated still ex-hibit MMCs. However, extrinsic neuralactivity can modify characteristics of theMMC.

Feeding abolishes MMCs and institutes apattern of more or less continuous contrac-tions of varying amplitude. The change inpattern caused by feeding probably isbrought about by hormones such as gastrin

and CCK, which are released during feed-ing, and by neural mechanisms.

VomitingVomiting (emesis) is the forceful expulsionof intestinal and gastric contents through themouth. General discharge of the autonomicnervous system precedes and accompaniesvomiting, with resulting copious salivation,sweating, rapid breathing, and an irregularheartbeat. In humans vomiting is usually, butnot necessarily, associated with the feeling ofnausea. Vomiting is normally preceded byretching, which is the pattern of activity thatovercomes the antireflux mechanisms of thegastrointestinal (GI) tract.

A wave of reverse peristalsis beginning inthe distal small intestine moves intestinal con-tents orad. Retching begins as this wavemoves through the duodenum. A retch beginswith a deep inspiration against a closed glot-tis and a strong contraction of the abdominalmuscles. This increases intra-abdominal pres-sure and decreases intrathoracic pressure, so

that the pressure gradient between theseportions of the GI tract may become as greatas 200 mm Hg. With each retch, the abdom-inal portion of the esophagus and a portionof the stomach actually slide through the hi-atus of the diaphragm and move into thethorax. A contraction of the antrum and con-tinued reverse peristalsis force the gastriccontents through a relaxed lower esophagealsphincter and into the flaccid esophagus. Asthe retch subsides, the stomach moves backinto the relaxed abdomen, and most of thecontents drain back into the stomach. Thecycle may be repeated several times, duringwhich the upper esophageal sphincter re-mains closed, thus preventing gastric con-tents from entering the pharynx or mouth.

Vomiting itself occurs after a sequence ofstronger or developed retches. A suddenstrong contraction of the abdominal musclesraises the diaphragm high into the thoraxand results in an increase in intrathoracicpressure that may equal 100 mm Hg. The

larynx and hyoid bone are then reflexivelydrawn forward, and the increased in-trathoracic pressure forces the contents ofthe esophagus past the upper esophagealsphincter and out of the mouth. Material re-maining in the esophagus empties into thestomach after the abdominal muscles relax.The cycle may be repeated until almost allthe contents have been expelled.

Vomiting can be induced by a variety ofdiverse stimuli, both peripheral and centralin origin. These include pain, foul odors, re-pulsive sights, and psychological factors act-ing at the level of the cerebral cortex. Agroup of receptors located in the floor of thefourth ventricle of the brain, which is outsidethe blood-brain barrier, constitutes achemoreceptor trigger zone that is activatedby emetics in the blood or cerebrospinal flu-id. Stimulation of this zone also occurs dur-ing motion sickness caused by unequal vesti-bular input. In addition, chemically respons-ive receptors occur in the GI tract and re-

spond to emetics such as ipecac. Vomiting isalso triggered by mechanical stimuli to theGI tract, such as induced by tickling the backof the throat and by distention or blockageof the stomach or intestines. All these stimuliconverge on neurons located in the medulla,which interact with additional medullaryneurons controlling retching. Electrical stim-ulation of neurons in these areas can causevomiting without retching or retchingwithout vomiting. In the normal situation,however, their activities are closely coordin-ated.

In general, vomiting is a protective mech-anism to rid the body of noxious or toxicsubstances. Prolonged vomiting, however,can cause severe problems in fluid and elec-trolyte balance, especially in children. Be-cause gastric juice contains relatively (toplasma) high concentrations of hydrogen(H+) and potassium (K+), these individualsmay develop metabolic alkalosis and hypo-kalemia.

CLINICALAPPLICATIONSPrimary disorders of small in-testine motility are rare. Thesmall intestine may be involvedin certain general disorders ofsmooth muscle of thegastrointestinal and urinarytracts. The cause of these disor-ders is unknown, but they mayhave a genetic basis in some pa-tients. When the disorder is clin-ically apparent, a patient will ap-pear to have episodes of intest-inal obstruction; however, theproblem seems to involve a fail-ure of propulsive motility ratherthan an obstruction. Thus thename idiopathic pseudo-ob-struction has been coined. Insome patients with this syn-drome, the smooth muscle cells

and interstitial cells of Cajal areinvolved. In other patients, histo-logic studies show changes in en-teric nerves.

Altered small intestinal motil-ity resulting in delayed transitfrequently accompanies a varietyof diseases and clinical condi-tions. Perhaps the most commonis the transient ileus or apparentparalysis of the small intestinesometimes seen after abdominalsurgery. However, intra-abdom-inal inflammation (e.g., pancre-atitis, appendicitis, abscess) mayproduce a similar picture. Sys-temic diseases such as diabetesmellitus and amyloidosis, meta-bolic alterations such as potassi-um depletion, and administra-tion of drugs, particularly antich-olinergics, all may have an ad-

verse effect on intestinal transit.Mixing probably is impaired aswell, although this is less clinic-ally apparent.

Alternatively, rapid intestinaltransit is seen in certain malab-sorptive states induced by infec-tious agents, allergic reaction,and various pharmacologicagents. In these conditions bothmotility and absorption are affec-ted. In most disease states it isnot clear whether changes inmotility are primary (caused bythe disease) or secondary(caused by the presence of unab-sorbed or secreted material).

CLINICAL TESTS

Auscultation to detect “bowelsounds” probably is the mostcommon means used to assessbowel activity. In addition, ob-serving the movement of bariumby x-ray studies and of isotopesby scintigraphy (see Chapter 4)can yield some information ontransit time through the smallbowel. Unfortunately, thesemethods are not precise. Ad-vances in technology have madethe recording of intraluminalpressures rather easy in normalpersons and in patients withminimal gastrointestinal dys-function. However, the inaccess-ibility of the small intestine andthe difficulty in placing intralu-minal sensors in patients withmajor dysmotility limit theroutine use of direct recordings

of intestinal contractions as a dia-gnostic tool.

Summary1. Movement of contents within the intestinallumen depends on the type of contraction.Segmenting contractions cause mixing andlocal circulation of contents. Peristaltic con-tractions cause net aboral transit.2. During digestion of a meal, most contrac-tions are of the segmenting type, with shortperistaltic contractions occurring randomly.During interdigestive periods, bursts of in-tense peristaltic contractions envelop each re-gion of the intestine approximately every 90minutes. Each burst appears to begin in thestomach and migrate aborally along the in-testine such that it reaches the terminal ileumin approximately 90 minutes. This activity iscalled the MMC.3. Intestinal slow waves are cyclic depolariza-tions and repolarizations of muscle cell mem-branes. At any locus of the intestine, slowwaves are present at a constant frequency

(i.e., approximately 12 cpm in the duodenumand 8 cpm in the ileum). At adjacent loci,slow waves appear to propagate aborally.4. Spike potentials are rapid fluctuations inmembrane potential that are superimposedon the depolarization phase of the slowwave. These potentials, not the slow wavesthemselves, initiate contractions of themuscle. Spike potentials do not accompanyevery slow wave. Their presence and patterndepend on the digestive state and on neuraland humoral activities.5. Enteric nerves coordinate both the typesand patterns of contractions. The phase of in-tense contractions of the MMC in the upperintestine may be initiated by the release ofmotilin. The conversion of the MMC patternto the digestive pattern may result in partfrom the release of hormones such as gastrinand CCK.6. Vomiting in humans usually involvesnausea and retching, which overcomes theantireflux mechanisms of the GI tract, and

occurs in response to a variety of stimuli thatare coordinated in the medulla.

KEY WORDS ANDCONCEPTSMyenteric/Auerbach plexusSegmentationLaw of the intestinesMigrating motor complexSlow wave activitySpike potentialsPeristaltic reflexIntestino-intestinal reflexIdiopathic pseudo-obstruction

Suggested ReadingsHasler, W. L., Small intestinal motilityJohnson, L. R.,

eds. Physiology of the Gastrointestinal Tract, ed 4,vol 1. San Diego: Elsevier, 2006.

Weisbrodt, N. W., Motility of the small intestineJohn-son, L. R., eds. Physiology of the GastrointestinalTract, ed 2, vol 1. New York: Raven Press, 1987.

Wingate, D. L. Backward and forward with the mi-grating complex. Dig Dis Sci. 1981; 26:641–666.

Motility of the LargeIntestine

Object ives

Describe the anatomy of the large intest-ine.Explain the function of the ileocecal reflex.Define a mass movement.Understand the motility of defecation andthe rectosphincteric reflex.Discuss the control of defecation and ex-plain the loss of control that occurs withsome spinal cord injuries.

Contractions of the large intestine are organ-ized to allow for optimal absorption of waterand electrolytes, net aboral movement ofcontents, and storage and orderly evacu-ation of feces.

Anatomic ConsiderationsAnatomically the human large intestine is di-vided into the following: the cecum; the as-cending, transverse, descending, and sig-moid colon; the rectum; and the anal canal.The muscular layers of the large intestine arecomposed of both longitudinally and circu-larly arranged fibers. Longitudinal fibers areconcentrated into three flat bands called thetaeniae coli. These run from the cecum to therectum, where the fibers fan out to form amore continuous longitudinal coat. The circu-lar layer of muscle fibers is continuous fromthe cecum to the anal canal, where it increasesin thickness to form the internal anal sphinc-ter. Overlapping and slightly distal to the in-ternal anal sphincter are layers of striatedmuscle. These striated muscle bundles makeup the external anal sphincter.

In humans the external features of the largeintestine differ from those of the small intest-

ine. In addition to the presence of taeniaecoli, the colon appears to be divided into seg-ments called haustra or haustrations ( Fig.6-1). Haustra probably are the result of struc-tural and functional properties of the colon.Points of concentration of muscular tissueand mucosal foldings can be found in colonsexamined post mortem.

FIGURE 6-1 Anatomy of the colon. Thecolon is shorter and of larger diameter thanthe small intestine. The longitudinal smoothmuscle is concentrated into three bands(taeniae coli) in all regions except therectum. Note that all regions except therectum possess haustra. The exact cause ofhaustration is not known. Haustra areformed partly by contractions of the circularmuscle; however, because they are stillpresent after death, some investigators be-lieve they have a permanent structuralbasis.

In addition, haustra are more prominentin areas of the colon that possess taeniae coli.Haustra are not fixed, however. Segmentalcolonic contractions appear, disappear, andform again at another locus. Thus haustralformation also has a dynamic component be-cause of the contractile activity of colonicmusculature.

The large intestine, like other areas of thebowel, is innervated by the autonomicnervous system (ANS). The enteric systemconsists partly of many nerve cell bodies andendings that lie between the circular and thelongitudinal muscle coats. In areas of thelarge intestine with taeniae, this myentericplexus is concentrated beneath them. Cellsof the myenteric plexus receive input from avariety of receptors within the intestine, aswell as by way of the extrinsic nerves. Axonsfrom these cells innervate the muscle lay-ers. Extrinsic innervation to the large intest-ine comes from both parasympathetic andsympathetic branches of the ANS. There are

two pathways of parasympathetic innerva-tion: the cecum and the ascending and trans-verse portions of the colon are innervatedby the vagus nerve; the descending and sig-moid areas of the colon and the rectum areinnervated by pelvic nerves from the sacralregion of the spinal cord. The pelvic nervesenter the colon near the rectosigmoid junc-tion and project orally and aborally withinthe plane of the myenteric plexus. These pro-jections, called shunt fascicles, innervatemyenteric nerves en route. The vagus andpelvic nerves consist primarily of pregangli-onic efferent fibers and many afferent fibers.The efferent fibers synapse with the nervecell bodies of the myenteric and other in-trinsic plexuses. The proximal regions of thelarge intestine are sympathetically innerv-ated by fibers that originate from the super-ior mesenteric ganglion. More distal regionsreceive input from the inferior mesentericganglion. The distal rectum and anal canalare innervated by sympathetic fibers from

the hypogastric plexus. Most of the sym-pathetic fibers are postganglionic efferentand afferent fibers. The external anal sphinc-ter, a striated muscle, is innervated by the so-matic pudendal nerves.

As in other regions of the gut, several di-verse chemicals serve as mediators at pre-synaptic and postsynaptic junctions withinthe autonomic innervation to the large in-testine. Acetylcholine (ACh) and tachykininssuch as substance P serve as major excitatorymediators, and nitric oxide (NO), vasoactiveintestinal peptide (VIP), and possibly aden-osine triphosphate (ATP) serve as major in-hibitory mediators. Transmission betweenthe pudendal nerves and the external analsphincter is mediated by ACh.

Contractions of theCecum and AscendingColonThe flow of contents from the small intestineinto the large intestine is intermittent and isregulated partly by a sphincteric mechanismat the ileocecal junction. A sensor placed inthe junction records pressures that are severalmillimeters of mercury (mm Hg) greater thanthose in the ileum or colon. The pressure isnot constant, however; the sphincter relaxesperiodically, and during this time ileal con-tractions propel contents into the large intest-ine ( Fig. 6-2, A). Once material reaches theproximal large intestine, it is acted on by awide variety of contractions. Most of thesecontractions are segmental, with durations of12 to 60 seconds. The pressures generated by

these contractions vary in amplitude, ran-ging between approximately 10 and 50 mmHg.

FIGURE 6-2 Intraluminal pressures recor-ded at the level of the ileocecal sphincter.Note the resting pressure of 20 to 40 mmHg. A, Distention of the ileum causessphincteric relaxation and thus allows flowof contents from the ileum into the colon. B,Distention of the colon, by contrast, causescontraction of the sphincter to prevent pas-sage of contents from the colon to theileum. (From Cohen S, Harris LD, Levitan R: Manometric

characteristics of the human ileocecal junctional zone.

Gastroenterology 54:72-75, 1968.)

It is believed that these contractions arepartly responsible for the haustrations seenin the colon. At adjacent sites, contractionsusually occur independently. Thus theyslowly move the contents back and forth,mixing and exposing them to the mucosa forabsorption of water and electrolytes. In ad-dition to pressure changes caused by seg-mental contractions, many of other pressurewaves have been recorded. Attempts to clas-sify these have been made, but the degree ofoverlap of pressure profiles makes classifica-tion difficult.

Occasionally, segmental contractions areorganized in an oral-to-aboral direction; thuspropulsion over short distances takes place.Usually, however, propulsion occurs duringa characteristic sequence termed mass move-ment. Segmental activity suddenly ceases,and along with its disappearance is a lossof haustrations. The colon then undergoesa contraction that sweeps intraluminal con-tents in an aboral direction ( Fig. 6-3, A to C).

After the mass movement, haustrations andphasic contractions return ( Fig. 6-3, D). Massmovements are infrequent in healthy peopleand are estimated to occur only one to threetimes daily. Because they are such infrequentevents, they have not been studied in anygreat detail in normal persons.

FIGURE 6-3 Two mass movements. A,Appearance of the colon before the entry ofbarium sulfate. B, As the barium enters fromthe ileum, it is acted on by haustral contrac-tions. C, As more barium enters, a portion isswept into and through an area of the colonthat has lost its haustral markings. D, Thebarium is acted on by the returning haustralcontractions. E, A second mass movement

propels the barium into and through areasof the transverse and descending colon. F,Haustrations again return. This type of con-traction accomplishes most of the move-ment of feces through the colon.

Contractions of theDescending and SigmoidColonBy the time material reaches the descendingand sigmoid colon, it has changed from a li-quid to a semisolid state. Although there isless absorption of water and electrolytes fromthese portions of the colon, motility studieshave demonstrated that contractions of thesegmenting type are more frequent here thanin the ascending and transverse colon. Thesesegmenting contractions do not result inpropulsion. On the contrary, they offer res-istance and thus retard the flow of contentsfrom more proximal regions into the rectum.Propulsion into and through these areas alsooccurs during mass movements. Here, too,there is a loss of segmental activity and thehaustrations that precede transport ( Fig. 6-3,

E and F). Thus material that enters these re-gions during a mass movement is acted on toreduce its liquid content further and is thenpropelled into the rectum during a subse-quent mass movement.

Motility of the Rectumand Anal CanalThe rectum usually is empty or nearly so. Al-though very little material is present, contrac-tions do occur in this region. In fact, the upperregions of the rectum contract segmentallymore frequently than does the sigmoid colon.This activity tends to retard the flow of con-tents into the rectum. When the rectum fills, itdoes so intermittently. During a mass move-ment or during an aborally directed sequenceof segmental contractions of the sigmoidcolon, some material passes into the rectum.

Normally the anal canal is closed becauseof contraction of the internal anal sphincter.When the rectum is distended by fecal ma-terial, however, the internal sphincter relaxesas part of the rectosphincteric reflex ( Fig.6-4). Rectal distention also elicits a sensationthat signals the urge for defecation. Defeca-

tion is prevented by the external anal sphinc-ter, which is normally in a state of tonic con-traction maintained by reflex activationthrough dorsal roots in the sacral segments.In paraplegic patients lacking this tonic con-traction, the rectosphincteric reflex results indefecation. In the normal individual, if en-vironmental conditions are not conducive todefecation, voluntary contractions of the ex-ternal sphincter can overcome the reflex.Relaxation of the internal sphincter is tran-sient because the receptors within the rectalwall accommodate the stimulus of disten-tion. Thus the internal anal sphincter regainsits tone, and the sensation subsides until thepassage of more contents into the rectum.The rectum can accommodate rather largequantities of material, so it acts as a storageorgan.

FIGURE 6-4 Intraluminal pressure recor-ded at the level of the internal and externalanal sphincters. Rectal distention causes re-laxation of the internal sphincter and con-traction of the external sphincter. Note,however, that the changes in sphinctericpressures are transient even though rectaldistention is maintained. This finding is re-lated to the accommodation of the stretch

receptors within the wall of the rectum. (Modi-

fied from Schuster MM, Hookman P, Hendrix TR: Simul-

taneous manometric recording of internal and external anal

sphincteric reflexes. Johns Hopkins Med J 116: 70-88,

1965.)

If the rectosphincteric reflex is elicited at atime when evacuation is convenient, defec-ation occurs. Defecation is accomplished bya series of voluntary and involuntary acts.When rectal distention is followed by defec-ation, muscles of the descending and sig-moid colon and the rectum may contract topropel contents toward the anal canal. Thenboth internal and external sphincters relax toallow passage of the bolus. Normally theseevents are accompanied by voluntary actsthat raise intra-abdominal pressure andlower the pelvic floor. Intra-abdominal pres-sure is increased by contractions of the dia-phragm and musculature of the abdominalwall. Simultaneously the musculature of thepelvic floor relaxes to allow the increased ab-

dominal pressure to force the floor down-ward.

Control of MotilityFactors that control motility of the large in-testine are complex and poorly understood.As in the stomach and small intestine, motil-ity in the large intestine is influenced by atleast four factors: interstitial cells of Ca-jal–smooth muscle properties, enteric nerves,extrinsic nerves, and circulating or locally re-leased chemicals.

The tone of the ileocecal sphincter is ba-sically myogenic. It is modified, however, bynervous and humoral factors. Distention ofthe colon causes an increase in sphincterictension, a reflex mediated by enteric nerves(see Fig. 6-2, B). Distention of the ileum causesrelaxation, also mediated by enteric nerves(see Fig. 6-2, A). Relaxation of the sphincterand an increase in the contractile activity ofthe ileum occur with or shortly after eating.This has been termed the gastroileal reflex.One view is that the reflex is mediated by

the gastrointestinal (GI) hormones, primarilygastrin and cholecystokinin (CCK). Boththese hormones cause an increase in the con-tractile activity of the ileum, as well as relax-ation of the ileocecal sphincter. Some invest-igators, however, think that this reflex is me-diated via the extrinsic autonomic nerves tothe intestine.

Smooth muscle cells of the ascending,transverse, descending, and sigmoid colonand of the rectum exhibit fluctuations intheir membrane potential. Cyclic depolariz-ations and repolarizations that possess someof the characteristics of small intestinal slowwaves can be recorded. As in the small in-testine, these slow waves are thought to de-pend on interactions between smoothmuscle cells and interstitial cells of Cajal.Potential changes that resemble spike poten-tials also are recorded. These changes prob-ably initiate contractions, but the exact rela-tionships between changes in potential andcontractile activity have not been clarified. In

addition, investigators have recorded vari-ous oscillations in membrane potential thatfit descriptions of neither slow wave norspike potential activities. The origin andfunction of these phenomena are less clear.

Enteric neurons are involved in the controlof colonic contractions; aperistaltic reflex canbe initiated in the colon, and this reflex ismediated by nerves within the myentericplexus. These plexal nerves seem to be pre-dominantly inhibitory because in their ab-sence the colon is contracted tonically. Sever-al colonic reflexes have their pathways in theextrinsic nerves. Distention of remote areasof the bowel induces an inhibition of con-tractions. The pathway for this reflex in-cludes the inferior mesenteric ganglion andalso may include the spinal cord. In addition,several investigations have demonstratedthat emotional state has a marked influenceon colonic motility. These influences of thecentral nervous system are mediated by theextrinsic nerves.

The GI hormones, as well as epinephrineand the prostaglandins, affect colonic motil-ity. Gastrin and CCK increase colonic activ-ity and have been implicated in the massmovement that sometimes occurs after eat-ing. Epinephrine inhibits all contractileactivity, whereas the prostaglandins(primarily E type) decrease segmenting con-tractions and increase propulsive activity.The importance of these agents in regulatingcolonic motility is not known.

The rectosphincteric reflex and the act ofdefecation are under neural control. Part ofthe control lies in the enteric nervous system.The reflex, however, is reinforced by activityof neurons within the spinal cord. Destruc-tion of the nerves to the anorectal area canresult in fecal retention. The sensation ofrectal distention, as well as voluntary controlof the external anal sphincter, is mediatedby pathways within the spinal cord that leadto the cerebral cortex. Destruction of these

pathways causes a loss of voluntary controlof defecation.

CLINICALSIGNIFICANCEAbnormal transit of materialthrough the colon is common.Delayed transit leads to constip-ation; in most situations,however, this is dietary in origin.There is a direct correlationamong increased dietary fiber,increased colonic intraluminalbulk, and enhanced transitthrough the colon. How motilityof the colon contributes to thesechanges in transit is not known.Laxatives work either by osmoticeffects (polyethylene glycol,magnesium citrate, lactulose,and sorbitol) or by increasingcolonic propulsion (bisacodyl,sodium picosulfate, and glycer-

ol). Alterations in motility andtransit are frequently caused byemotional factors and are indic-ative of the strong influence ofthe higher centers of the centralnervous system on motility. Thefinal effects of stress on colonicmotility vary greatly from indi-vidual to individual. Most stu-dents are familiar with diarrheaprevious to an important exam-ination. The severity of the prob-lem is usually related inverselyto how well the student is pre-pared for the test.

A particularly interesting anddramatic clinical disorder inwhich severe constipation is seenis congenital megacolon(Hirschsprung’s disease), whichis characterized by an absence ofthe enteric nervous system in the

distal colon. The internal analsphincter is always involved,and often the disease extendsproximally into the rectum. Theinvolved segment exhibits in-creased tone, has a very narrowlumen, and is devoid of propuls-ive activity. As a result, the colonproximal to the diseased seg-ment becomes dilated, thus pro-ducing a megacolon. This condi-tion is treated through surgicalremoval of the diseased segment.

In adults, the most commongastrointestinal disorder forwhich medical advice is soughtis irritable bowel syndrome.This disorder gives rise most of-ten to abdominal pain andaltered bowel habit (constipationand/or diarrhea). In limited ob-servations, exaggerated seg-

mental contractions in the sig-moid colon have been seen, par-ticularly in response to stimu-lants such as morphine. Duringstress, patients with irritablebowel syndrome and constipa-tion exhibit increased segmenta-tion in the sigmoid colon, where-as those with diarrhea exhibit de-creased segmentation. In addi-tion to motility disorders, sens-ory hypersensitivity to visceralstimulation may play a role. Thecause of this disorder remainsunknown. One theory suggeststhat altered motility may reflectthe conditioning of autonomicresponses from repeated expos-ure to stressful situations. Anoth-er suggests that gastrointestinalinfections and alterations in nor-mal colonic flora play a role in

the origin of irritable bowel syn-drome.

In older age groups, divertic-ula (outpouchings of mucosathat extend through the muscu-lar wall) frequently develop inthe colon. Evidence suggests thatabnormal colonic motility leadsto diverticulum formation be-cause of the generation of in-creased intraluminal pressure.However, a direct correlationamong abnormal motility, symp-toms, and the presence of diver-ticula cannot always be demon-strated.

CLINICAL TESTSDespite the large numbers of pa-tients in whom disordered colon-

ic motility is suspected, tech-niques for monitoring contrac-tions are not in general clinicaluse. Most often, radiologic pro-cedures are used to provide lim-ited information. In one test, ra-diopaque markers are ingesteddaily for 3 days. On the fourthday, a radiograph is taken, andthe number of markers in eachregion of the colon is noted andcompared with normal values.Measurements of intraluminalpressures and myoelectric activ-ity are feasible, especially in thesigmoid colon and rectum, be-cause these areas are readily ac-cessible. To date, such tech-niques are mainly used in invest-igative studies.

The behavior of both the in-ternal and the external anal

sphincters, and the response torectal distention, can be meas-ured by the careful placement oftwo small intraluminal balloonsin the anal canal. A third balloonis placed in the rectum and is dis-tended to monitor the compon-ents of the defecation reflex. Thistechnique is useful in patientswith suspected neurologic disor-ders that result in impaired de-fecation.

Summary1. The muscular anatomy of the colon is char-acterized by concentration of the longitudinalmuscle into bands called taeniae coli. Con-traction of the taeniae coli and the circularmuscle results in haustrations.2. Most colonic contractions are of the seg-menting type, which aid in the absorption ofwater and electrolytes. The frequency of seg-menting contractions is higher in the descend-ing and sigmoid colon than in areas locatedmore orad. This retards aboral progression.3. Aboral movement of contents is slow, usu-ally taking days to pass material through thecolon. Most aboral movement takes placeduring infrequent peristaltic contractionscalled mass movements.4. Tonic contraction of the internal analsphincter maintains closure of the anal canal.Distention of the rectum elicits relaxation ofthe internal anal sphincter and causes the

urge to defecate. Defecation can be preven-ted by voluntary contraction of the externalanal sphincter while the rectum accommod-ates to the distention and the internal analsphincter regains its tone. Relaxation of theexternal anal sphincter during this timeleads to defecation.5. Colonic slow waves are cyclic depolariz-ations and repolarizations of muscle cellmembranes that appear to set the timing ofsegmental contractions. Neural activity andhormone levels influence the intensity ofsegmental contractions.6. Mass movements are regulated by activit-ies of the intrinsic and extrinsic nerves andpossibly by the hormones gastrin and CCK.The rectosphincteric reflex is regulated byintrinsic, extrinsic autonomic, and somaticnerves.

KEY WORDS ANDCONCEPTSCecum

Ascending/transverse/descend-ing/sigmoid colonRectumAnal canalTaeniae coliInternal anal sphincterExternal anal sphincterHaustra/haustrationsShunt fasciclesIleocecal junctionMass movementRectosphincteric reflexDefecationGastroileal reflexConstipationHirschsprung’s diseaseIrritable bowel syndromeDiverticula

Suggested ReadingsBharucha, A. E., Brookes, S. J. H., Neurophysiologic

mechanisms of human large intestinal motil-ityJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 1. San Diego: El-sevier, 2012.

Christensen, J., The motility of the colonJohnson, L.R., eds. Physiology of the Gastrointestinal Tract,ed 3, vol 1. New York: Raven Press, 1994.

Phillips, S. F., Motility disorders of the colonYamada,T., Alpers, D. H., Laine, L., et al, eds. Textbook ofGastroenterology, ed 3, vol 1. Philadelphia: Lip-pincott Williams & Wilkins, 1999.

Sarna, S., Large intestinal motilityJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 4, vol1. San Diego: Elsevier, 2006.

Salivary Secretion

Object ives

Discuss the constituents and various func-tions of saliva.Understand the mechanisms leading to theformation of saliva.Explain the processes resulting in the ton-icity of saliva and concentrations of its vari-ous ions.Describe the regulation of salivary secre-tion.

Although the salivary glands are not essen-tial to life, their secretions are important forthe hygiene and comfort of the mouth andteeth. The functions of saliva may be dividedinto those concerned with lubrication, pro-tection, and digestion. An active processproduces saliva in large quantities relative tothe weight of the salivary glands. Saliva ishyposmotic at all rates of secretion, and incontrast to the other gastrointestinal (GI) se-cretions, the rate of secretion is almost totallyunder the control of the nervous system.Another characteristic of this regulation isthat both branches of the autonomic nervoussystem (ANS) stimulate secretion. However,the parasympathetic system provides amuch greater stimulus than does the sym-pathetic system.

Functions of SalivaThe lubricating ability of saliva dependsprimarily on its content of mucus. In themouth, mixing saliva with food lubricates theingested material and facilitates the swallow-ing process. The lubricating effect of saliva isalso necessary for speech, as evidenced by theglass of water normally found on the podiumof a public speaker.

Saliva exerts its effects through a variety ofdifferent mechanisms. It protects the mouthby buffering and diluting noxious substances.Hot solutions of tea, coffee, or soup, for ex-ample, are diluted and cooled by saliva. Foul-tasting substances can be washed from themouth by copious salivation. Similarly, thesalivary glands are stimulated strongly beforevomiting. The corrosive gastric acid and pep-sin that are brought up into the esophagusand mouth are thereby neutralized and di-luted by saliva. Dry mouth, or xerostomia, is

associated with chronic infections of the buc-cal mucosa and with dental caries. Salivadissolves and washes out food particles frombetween the teeth. Certain specialized con-stituents of saliva have antibacterial actions.These include the following: a lysozyme,which attacks bacterial cell walls; lactofer-rin, which chelates iron and thus preventsthe multiplication of organisms that requireit for growth; and the binding glycoproteinfor immunoglobulin A (IgA), which in com-bination with IgA forms secretory IgA,which in turn is immunologically activeagainst viruses and bacteria. Various inor-ganic compounds are taken up by thesalivary glands, concentrated, and secretedin saliva. These include fluoride and calcium(Ca2+), which are subsequently incorporatedinto the teeth.

The contributions made by saliva to nor-mal digestion include dissolving and wash-ing away food particles on the taste buds toenable one to taste the next morsel of food

eaten. Saliva contains two enzymes, one dir-ected toward carbohydrates and the othertoward fat. An α-amylase called ptyalincleaves internal α-1,4-glycosidic bondspresent in starch. Exhaustive digestion ofstarch by this enzyme, identical to pancreaticamylase, produces maltose, maltotriose, andα-limit dextrins, which contain the α-1,6branch points of the original molecule.Salivary amylase has a pH optimum of 7,and it is rapidly denatured at pH 4.However, because a large portion of a mealoften remains unmixed for a considerablelength of time in the orad stomach, thesalivary enzyme may account for the diges-tion of as much as 75% of the starch presentbefore it is denatured by gastric acid. In theabsence of salivary amylase, there is no de-fect in carbohydrate digestion because thepancreatic enzyme is secreted in amountssufficient to digest all the starch present.

The serous salivary glands of the tonguesecrete the second digestive enzyme, lingual

lipase, which plays a role in the hydrolysisof dietary lipid. Unlike pancreatic lipase, lin-gual lipase has properties that allow it to actin all parts of the upper GI tract. Thus theability of lingual lipase to hydrolyze lipidsis not affected by surface-active detergentssuch as bile salts, medium chain fatty acids,and lecithin. It has an acidic pH optimumand remains active through the stomach andinto the intestine.

Anatomy and Innervationof the Salivary GlandsThe salivary glands are a collection of some-what dissimilar structures in the mouth thatproduce a common juice (the saliva), al-though the composition of the secretion fromdifferent salivary glands varies. The largest ofthe salivary structures are the paired parot-id glands, located near the angle of the jawand the ear. They are serous glands, secretea fairly watery juice rich in amylase, and ac-count for approximately 25% of the daily out-put of saliva. The smaller bilateral sub-mandibular and sublingual glands aremixed glands, containing both serous andmucous cells. They elaborate a more viscidsaliva and secrete most of the remaining 75%of the output. Other, still smaller glands arepresent in the mucosa covering the palate,buccal areas, lips, and tongue.

Most of the salivary glands are ectodermalin origin. The combined secretion of the pa-rotid and submandibular glands constitutes90% of the volume of saliva, which in a nor-mal adult can amount to a liter daily. Thespecific gravity of this mixed juice rangesfrom 1.000 to 1.010.

The microscopic structure of the salivaryglands combines many features observed inanother exocrine gland, the pancreas. Asalivary gland consists of a blind-end systemof microscopic ducts that branch out fromgrossly visible ducts. One main duct opensinto the mouth from each gland. The func-tional unit of the salivary duct system, thesalivon, is depicted in Figure 7-1. At theblind end is the acinus, surrounded by poly-gonal acinar cells. These cells secrete the ini-tial saliva, including water, electrolytes, andorganic molecules such as amylase. Thesolutes and fluid move out of the acinar cellinto the duct lumen to form the initial saliva.The acinar cells are surrounded in turn by

myoepithelial cells. The myoepithelial cellsrest on the basement membrane of acinarcells. They contain an actinomycin and havemotile extensions. The next segment of thesalivon is the intercalated duct, which maybe associated with additional myoepithelialcells. Contraction of myoepithelial cellsserves to expel formed saliva from theacinus, oppose retrograde movement of thejuice during active secretion of saliva,shorten and widen the internal diameter ofthe intercalated duct (thereby lowering res-istance to the flowing saliva), and preventdistention of the acinus (distention of theblind end of the salivon would permit back-diffusion of formed saliva through thestretched surface of the acinus). Thus themyoepithelial cells support the acinusagainst the increased intraluminal pressuresthat occur during secretion.

FIGURE 7-1 Cells lining the various por-tions of the salivon.

Whenever there is an abrupt need forsaliva in the mouth (e.g., immediately beforevomiting), myoepithelial cell contractionpropels the secretion into the main duct ofthe gland. Other exocrine glands, such as themammary glands and the pancreas, alsopossess myoepithelial cells.

The intercalated duct soon widens to be-come the striated duct, lined by columnarepithelial cells that resemble the epithelialcomponents of the renal tubule in both shapeand function. The saliva in the intercalatedduct is similar in ionic composition toplasma. Changes from that composition oc-cur because of ion exchanges in the striatedduct. As saliva traverses the striated duct,sodium (Na+) is actively reabsorbed from thejuice, and potassium (K+) is transported intoit. Ca2+ also enters secreting duct cells duringsalivation. Similarly, anionic exchange oc-curs; chloride (Cl−) is reabsorbed from the

saliva, and bicarbonate ( ) is added toit.

The striated duct epithelium is consideredto be a fairly “tight” sheet membrane. Thatis, its surface is fairly impermeable to theback-diffusion of water from the saliva intothe tissue, and osmotic gradients developbetween the saliva and interstitial fluid

through the reabsorption of Na+ and Cl−. Theresult is hypotonic saliva.

The blood supplied to the salivary glandsis distributed by branches of the external ca-rotid artery. The direction of arterial flowwithin each salivary gland is opposite thedirection of flowing saliva within the ductsof each salivon. The arterioles break up intocapillaries around the acini, as well as innonacinar areas. Blood from nonacinar areaspasses through portal venules back to theacinar capillaries, from which a second set ofvenules then drains all the blood to the sys-temic venous circulation. The rate of bloodflow through resting salivary tissue is ap-proximately 20 times that through muscle.This blood flow in part accounts for theprodigious amounts of saliva produced rel-ative to the weight of the glands.

Both components of the ANS reach thesalivary glands. The parasympatheticpreganglionic fibers are delivered by the fa-cial and glossopharyngeal nerves to auto-

nomic ganglia, from which the postgangli-onic fibers pass to individual glands. Thesympathetic preganglionic nerves originateat the cervical ganglion, whose postgangli-onic fibers extend to the glands in the peri-arterial spaces (these relationships appear inFig. 7-2). Parasympathetic and sympatheticmediators regulate all known salivary glandfunctions to an extraordinary degree. Theirinfluence includes major effects, not only onsecretion but also on blood flow, ductularsmooth muscle activity, growth, and meta-bolism of the salivary glands.

FIGURE 7-2 Autonomic nervous distribu-tion to the major salivary glands.

Composition of SalivaThe major constituents of saliva are water,electrolytes, and a few enzymes. The uniqueproperties of this GI juice are (1) its largevolume relative to the mass of glands thatsecrete saliva, (2) its low osmolality, (3) itshigh K+ concentration, and (4) the specific or-ganic materials it contains.

Inorganic CompositionCompared with other secretory organs of theGI tract, the salivary glands elaborate a re-markably large volume of juice per gram (g)of tissue. Thus, for example, an entire pan-creas may reach a maximal rate of secretionof 1 milliliter (mL)/minute, whereas at thehighest rates of secretion in some animals, atiny submaxillary gland can secrete 1 mL/g/minute, a 50-fold higher rate. In humans, thesalivary glands secrete at rates severalfold

higher than other GI organs per unit weightof tissue.

The osmolality of saliva is significantlylower than that of plasma at all but thehighest rates of secretion, when the saliva be-comes isotonic with plasma. As the secretoryrate of the salivon increases, the osmolalityof its saliva also increases.

The concentrations of electrolytes in salivavary with the rate of secretion ( Fig. 7-3). TheK+ concentration of saliva is 2 to 30 timesthat of the plasma, depending on the rateof secretion, the nature of the stimulus, theplasma K+ concentration, and the level ofmineralocorticoids in the circulation. Salivahas the highest K+ concentration of any di-gestive juice; maximal concentration valuesapproach those within cells. These remark-able levels of salivary K+ imply the existenceof an energy-dependent transport mechan-ism within the salivon. In most species theconcentration of Na+ in saliva is always less

than that in plasma, and, as the secretoryrate increases, the Na+ concentration also in-creases. In general, Cl− concentrations paral-lel those of Na+. These findings suggest thatNa+ and Cl− are secreted and then reabsorbedas the saliva passes through the ducts. The

concentration of in saliva is higherthan that in plasma, except at low flow rates.This also accounts for the changes in the pHof saliva. At basal rates of flow the pH isslightly acidic but rapidly rises to approxim-ately 8 as flow is stimulated. The relation-ships between ion concentrations and flowrates (shown in Fig. 7-3) vary somewhat, de-pending on the stimulus.

FIGURE 7-3 Concentrations of major ionsin the saliva as a function of the rate ofsalivary secretion. Values in plasma areshown for comparison. Cl−, chloride;

, bicarbonate; K+, potassium; Na+,sodium.

The relationships shown in Figure 7-3 areexplained by two basic types of studies thatindicate how the final saliva is produced.First, fluid collected by micropuncture of the

intercalated ducts contains Na+, K+, Cl−, and

in concentrations approximatelyequal to their plasma concentrations. Thisfluid also is isotonic to plasma. Second, ifone perfuses a salivary gland duct with fluidcontaining ions in concentrations similar tothose of plasma, Na+ and Cl− concentrations

are decreased and K+ and concen-trations are increased when the fluid is col-lected at the duct opening. The fluid also be-comes hypotonic, and the longer the fluid re-mains in the duct (i.e., the slower the rateof perfusion), the greater are the changes.These data indicate, first, that the acinisecrete a fluid similar to plasma in its con-centration of ions and, second, that as thefluid moves down the duct, Na+ and Cl− are

reabsorbed and K+ and are secretedinto the saliva. The higher the flow of saliva,the less time is available for modification,and the final saliva more closely resembles

plasma in its ionic makeup (see Fig. 7-3). Atlow flow rates K+ increases considerably, andNa+ and Cl− decrease. Because most salivary

agonists stimulate secretion, the

concentration remains relativelyhigh, even at high rates of secretion. Some

K+ and are reabsorbed in exchangefor Na+ and Cl−, but much more Na+ and Cl−

leave the duct, thus causing the saliva to be-come hypotonic. Because the duct epitheli-um is relatively impermeable to water, thefinal product remains hypotonic. These pro-cesses are depicted in Figure 7-4.

FIGURE 7-4 Movements of ions and water(H2O) in the acinus and duct of the salivon.

Cl−, chloride; , bicarbonate; K+,potassium; Na+, sodium.

Current evidence indicates that Cl− is theprimary ion that is actively secreted by theacinar cells ( Fig. 7-5). No evidence existsfor direct active secretion of Na+. The secret-ory mechanism for Cl− is inhibited by ou-abain, a finding indicating that it dependson the Na+/K+ pump in the basolateral mem-brane. The active pumping of Na+ out of the

cell creates a diffusion gradient for Na+ toenter across the basolateral membrane. Twomain ion transport pathways exploit this Na+

gradient to accumulate Cl− above its equi-librium potential. In the first (see Fig. 7-5,cell 1), 2Cl− are cotransported with Na+ andK+ into the cell to preserve electrical neutral-ity. This process increases the electrochemic-al potential of Cl− within the cell, and Cl− dif-fuses down this gradient into the lumen viaan electrogenic ion channel that may also al-

low to enter the lumen. Inhibitionof the Na+/K+/2Cl− cotransporter decreasessalivary secretion by 65%. In the second (seeFig. 7-5, cell 2), Na+ enters in exchange forhydrogen (H+), which alkalinizes the cellpromoting the intracellular accumulation of

, which then is exchanged for Cl−.

Removal of from the perfusate orinhibition of the Na+/H+ exchanger by ami-loride reduces secretion by 30%. In both

cases Na+ moves paracellularly through thetight junctions and into the lumen, thus pre-serving electroneutrality; water followsdown its osmotic gradient. Evidence indic-ates that water also moves into the salivatranscellularly through the aquaporin 5 apic-al water channel. There may also be a Ca2+-activated K+ channel in the basolateral mem-brane. Exodus of K+ increases the electroneg-ativity of the cytosol and thereby increasesthe driving force for the entry of Cl− and

into the lumen. Agents that stimu-late salivary secretion increase the activity ofall these channels and transport processes.

FIGURE 7-5 Intracellular mechanisms forthe movement of ions in the acinar cells of

the salivary glands. Cl−, chloride; ,bicarbonate; H2O, water; K+, potassium;Na+, sodium.

Within the ducts, Na+ and Cl− are actively

absorbed and K+ and are activelysecreted ( Fig. 7-6). These processes are alsoinhibited by ouabain and depend on the Na+

gradient created by the Na+, K+-adenosinetriphosphatase (ATPase) in the basolateralmembrane. The apical membrane contains aNa+ channel, and its movement into the cellsupports the electrogenic movement of Cl−

into the cell through Cl− channels. The Na/K-ATPase pumps Na+ out while a Cl− chan-nel in the basolateral membrane transports itout of the cell. Cl− reabsorption also occursvia the paracellular pathway. K+ is secretedthrough apical channels into the saliva. To

secrete into the lumen,must be concentrated within the cell. This

occurs via an Na/ transporter in thebasolateral membrane, which is driven by

the Na+ gradient. leaves the celleither through the apical cyclic adenosinemonophosphate (cAMP)-activated CFTR(cystic fibrosis transmembrane regulator)

Cl− channel or via the Cl−/ exchangerat the apical membrane. The tight junctionsof the ductule epithelium are relatively im-permeable to water when compared withthose of the acini. The net results are a de-crease in Na+ and Cl− concentrations and an

increase in K+ and concentrations,as well as pH, as the saliva moves down theduct. More ions leave than water (H2O), andthe saliva becomes hypotonic. Aldosteroneacts at the luminal membrane to increase the

absorption of Na+ and the secretion of K+ byincreasing the numbers of their channels.

FIGURE 7-6 Intracellular mechanisms forthe movement of ions in ductule cells of the

salivary glands. Cl−, chloride; , bi-carbonate; K+, potassium; Na+, sodium.

Organic CompositionSome organic materials produced andsecreted by the salivary glands are men-tioned earlier in the section on the functionsof saliva. These materials include the en-zymes α-amylase (ptyalin) and linguallipase, mucus, glycoproteins, lysozymes,and lactoferrin. Another enzyme producedby salivary glands is kallikrein, which con-verts a plasma protein into the potent vas-odilator bradykinin. Kallikrein is releasedwhen the metabolism of the salivary glandsincreases; it is responsible in part for in-creased blood flow to the secreting glands.Saliva also contains the blood group sub-stances A, B, AB, and O.

The synthesis of salivary gland enzymes,their storage, and their release are similar to

the same processes in the pancreas (detailedin Chapter 9). The protein concentration ofsaliva is approximately one tenth the con-centration of proteins in the plasma.

Regulation of SalivarySecretionThe ANS controls essentially all salivarygland secretion. Antidiuretic hormone(ADH), or vasopressin, and aldosteronemodify the composition of saliva by decreas-ing its Na+ concentration and increasing itsK+ concentration, but they do not regulate theflow of saliva. The absence of hormonal con-trol of salivation contrasts with the regulationof the flow of gastric and pancreatic juice andbile. The GI hormones exert major influenceson the secretory activity of the stomach, pan-creas, and liver. Control of the salivary glandsis also unusual in that both the parasympath-etic and sympathetic branches stimulate se-cretion. The parasympathetic system,however, exerts a much greater influence.

Stimulation of the parasympathetic nervesto the salivary glands begins and maintains

salivary secretion. Increased secretion res-ults from the activation of transport pro-cesses in both acinar and duct cells. Secretionis enhanced by the contraction of the myoep-ithelial cells that are innervated by the para-sympathetic nerves. Parasympathetic fibersalso innervate the surrounding blood ves-sels, thus stimulating vasodilation and in-creasing blood flow to the secreting cells. In-creased cellular activity in response to para-sympathetic stimulation results in higherconsumption of glucose and oxygen and inthe production of vasodilator metabolites. Inaddition, kallikrein is released, resulting inthe production of the vasodilator bra-dykinin. Increased cellular activity eventu-ally leads to growth of the salivary glands.Section of the parasympathetic nerves to thesalivary glands causes the glands to atrophy.These processes are outlined in Figure 7-7.

FIGURE 7-7 Summary of the regulation ofsalivary gland function. ACh, acetylcholine;cAMP, cyclic adenosine monophosphate;Ca2+, calcium; CN, cranial nerve; IP3, inosit-ol triphosphate; Norepi, norepinephrine.

Sympathetic activation also stimulates se-cretion, myoepithelial cell contraction, meta-

bolism, and growth of the salivary glands,although these effects are less pronouncedand of shorter duration than are those pro-duced by the parasympathetic nerves. Stim-ulation via the sympathetic nerves producesa biphasic change in blood flow to thesalivary glands. The earliest response is a de-crease caused by activation of α-adrenergicreceptors and vasoconstriction. However, asvasodilator metabolites are produced, bloodflow increases over resting levels. Section ofthe sympathetic fibers to the salivary glands,unlike section of the parasympathetic fibers,has little effect. The effects of sympatheticstimulation also are summarized in Figure7-7.

Salivary glands contain receptors to manymediators, but the most important function-ally are the muscarinic cholinergic and β-ad-renergic receptors. The parasympathetic me-diator is acetylcholine (ACh), which acts onmuscarinic receptors and thereby results inthe formation of inositol triphosphate (IP3)

and the subsequent release of Ca2+ from in-tracellular stores. Ca2+ also may enter the cellfrom outside. Other agents that are releasedfrom neurons in salivary glands and that re-lease Ca2+ include vasoactive intestinal pep-tide (VIP) and substance P. The primarysympathetic mediator is norepinephrine,which binds to β-adrenergic receptors, a pro-cess resulting in the formation of cAMP.Formation of these second messengerscauses protein phosphorylation and enzymeactivation that ultimately leads to the stimu-lation of the salivary glands. In general, ag-onists that release Ca2+ have a greater effecton the volume of acinar cell secretion,whereas those elevating cAMP lead to agreater increase in enzyme and mucus con-tent.

The dual autonomic regulation of thesalivary glands is unusual in that both theparasympathetic and sympathetic systemsstimulate secretory, metabolic, trophic, mus-

cular, and circulatory functions in similardirections. Their complementary effects areshown in Figure 7-7.

Ultimately, the central nervous systemand its autonomic arms are what respond toexternal events and either stimulate or in-hibit activities of the salivary glands. Com-mon events leading to increased glandularactivities include chewing, consuming spicyor sour-tasting foods, and smoking. Externalevents leading to glandular inhibition in-clude sleep, fear, dehydration, and fatigue.Glandular activities sensitive to neural con-trol include secretion, circulation, myoep-ithelial contraction, cellular metabolism, andeven parenchymal growth.

CLINICALCORRELATIONMedical conditions can altereither the amount or the compos-ition of saliva. Mumps is a com-mon childhood infection of the

salivary glands that results inswelling, which can affect saliva-tion. Besides congenital xerosto-mia (absence of saliva), there isSjögren’s syndrome, an acquireddisease characterized by atrophyof the glands and decreased sal-ivation. The commonly useddrugs of the digitalis familycause increased concentrationsof calcium and potassium insaliva. In patients with cysticfibrosis, salivary sodium, calci-um, and protein concentrationsare elevated (as are these com-ponents in the bronchial secre-tions, pancreatic juice, and sweatof patients with this disease).Salivary sodium concentrationsalso are elevated in Addison’sdisease, but they are decreased inCushing’s syndrome, in primary

aldosteronism, and during preg-nancy. These electrolytic changesin saliva reflect events or dis-eases that make similar altera-tions in other bodily secretions.Excessive salivation is observedin patients with tumors of themouth or esophagus and in Par-kinson’s disease. In these cases,unusual local, reflexive, andmore general neurologic stimuliare responsible.

Summary1. The functions of saliva include those con-cerned with digestion, protection, and lubric-ation.2. Saliva is noteworthy in that it is producedin large volumes relative to the weight of theglands, is hypotonic, and contains relativelyhigh concentrations of K+.3. The primary saliva is produced in endpieces called acini and is then modified as itpasses through the ducts.4. Acinar secretion contains ions and water inconcentrations approximately equal to thosein plasma.5. Within the ducts, Na+ and Cl− are reab-

sorbed, and K+ and are secreted.6. Because the ductule epithelium is relativelyimpermeable to water and ions, the saliva be-comes more hypotonic as it moves throughthe ducts.

7. All regulatory control of salivation isprovided by the ANS, and both the parasym-pathetic and sympathetic branches stimulatesecretion and metabolism of the glands.

KEY WORDS ANDCONCEPTSLubricationProtectionDigestionMucusLysozymeLactoferrinBinding glycoprotein for im-munoglobulin Aα-AmylasePtyalinLingual lipaseParotid glandsSubmandibular/sublingualglandsSalivonAcinus

Myoepithelial cellsIntercalated ductStriated ductUnique propertiesKallikreinBradykinin

Suggested ReadingsCook, D. I., van Lennep, E. W., Roberts, M., et al, Se-

cretion by the major salivary glandsJohnson, L.R., eds. Physiology of the Gastrointestinal Tract,ed 3, vol 2. New York: Raven Press, 1994.

Melvin, J. E., Culp, D. J., Salivary glands,physiologyJohnson, L. R., eds. Encyclopedia ofGastroenterology; vol 3. Academic Press, SanDiego, 2004:318–325.

Catalan, M. A., Ambatipudi, K. S., Melvin, J. E.,Salivary gland secretionJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

Gastric Secretion

Object ives

Identify the secretory products of the stom-ach, their cells of origin, and their functions.Understand the mechanisms making itpossible for the stomach to secrete 150 mNhydrochloric acid.Describe the electrolyte composition ofgastric secretion and how it varies with therate of secretion.Identify the major stimulants of the parietalcell and explain their interactions.

Discuss the phases involved in the stimu-lation of gastric acid secretion and the pro-cesses acting in each.Identify factors that both stimulate and in-hibit the release of the hormone gastrin.Explain the processes that result in the in-hibition of gastric acid secretion followingthe ingestion of a meal and its emptyingfrom the stomach.Describe the processes resulting in gast-ric and duodenal ulcer diseases.

Five constituents of gastric juice—intrinsicfactor, hydrogen ion (H+), pepsin, mucus,and water—have physiologic functions.They are secreted by the various cellspresent within the gastric mucosa. The onlyindispensable ingredient in gastric juice isintrinsic factor, required for the absorptionof vitamin B12 by the ileal mucosa. Acid is

necessary for the conversion of inactivepepsinogen to the enzyme pepsin. Acid andpepsin begin the digestion of protein, butin their absence pancreatic enzymes hydro-lyze all ingested protein, so no nitrogen iswasted in the stools. Acid also kills a largenumber of bacteria that enter the stomach,thereby reducing the number of organismsreaching the intestine. In cases of severely re-duced or absent acid secretion, the inciden-ce of intestinal infections is greater. Mucuslines the wall of the stomach and protects itfrom damage. Mucus acts primarily as a lub-ricant, protecting the mucosa from physical

injury. Together with bicarbonate (), mucus neutralizes acid and maintains thesurface of the mucosa at a pH near neutral-ity. This is part of the gastric mucosal barrierthat protects the stomach from acid and pep-sin digestion. Water acts as the medium forthe action of acid and enzymes and solubil-izes many of the constituents of a meal.

Gastric juice and many of its functions ori-ginally were described by a young army sur-geon, William Beaumont, stationed at a forton Mackinac Island in northern Michigan.Beaumont was called to treat a French Cana-dian, Alexis St. Martin, who had been acci-dentally shot in the side at close range witha shotgun. St. Martin unexpectedly survivedbut was left with a permanent opening intohis stomach from the outside (gastric fistula).The accident occurred in 1822, and duringthe ensuing 3 years Beaumont nursed St.Martin back to health. Beaumont retained St.Martin “for the purpose of making physiolo-gical experiments,” which were begun in1825. Beaumont’s observations and conclu-sions, many of which remain unchangedtoday, include the description of the juice it-self and its digestive and bacteriostatic func-tions, the identification of the acid as hydro-chloric, the realization that mucus was a sep-arate secretion, the realization that mentaldisturbances affected gastric function, a dir-

ect study of gastric motility, and a thoroughstudy of the ability of gastric juices to digestvarious foodstuffs.

Functional AnatomyFunctionally, the gastric mucosa is dividedinto the oxyntic gland area and the pyloricgland area ( Fig. 8-1). The oxyntic gland mu-cosa secretes acid and is located in the prox-imal 80% of the stomach. It includes the bodyand the fundus. The distal 20% of the gastricmucosa, referred to as the pyloric gland mu-cosa, synthesizes and releases the hormonegastrin. This area of the stomach often is des-ignated the antrum.

FIGURE 8-1 Areas of the stomach.

The gastric mucosa is composed of pitsand glands ( Fig. 8-2). The pits and surfaceitself are lined with mucous or surface epi-thelial cells. At the base of the pits are theopenings of the glands, which project intothe mucosa toward the outside or serosa.The oxyntic glands contain the acid-produ-cing parietal cells and the peptic or chiefcells, which secrete the enzyme precursorpepsinogen. Pyloric glands contain the

gastrin-producing G cells and mucous cells,which also produce pepsinogen. Mucousneck cells are present where the glands openinto the pits. Each gland contains a stem cellin this region. These cells divide; one daugh-ter cell remains anchored as the stem cell,and the other divides several times. The res-ulting new cells migrate both to the surface,where they differentiate into mucous cells,and down into the glands, where they be-come parietal cells in the oxyntic gland area.Endocrine cells such as the G cells also differ-entiate from stem cells. Peptic cells are cap-able of mitosis, but evidence indicates thatthey also can arise from stem cells duringthe repair of damage to the mucosa. Cells ofthe surface and pits are replaced much morerapidly than are those of the glands.

FIGURE 8-2 Oxyntic gland and surfacepit. Note the positions of the various celltypes.

The parietal cells secrete hydrochloric acid(HCl) and, in humans, intrinsic factor. Insome species the chief cells also secrete in-trinsic factor. The normal human stomachcontains approximately 1 billion parietalcells, which produce acid at a concentrationof 150 to 160 mEq/L. The number of parietalcells determines the maximal secretory rateand accounts for interindividual variability.The human stomach secretes 1 to 2 L of gast-ric juice per day. Because the pH of the finaljuice at high rates of secretion may be lessthan 1 and that of the blood is 7.4, the pari-etal cells must expend a large amount of en-ergy to concentrate H+. The energy for theproduction of this more than a million foldconcentration gradient comes from aden-osine triphosphate (ATP), which is produced

by the numerous mitochondria located with-in the cell ( Fig. 8-3).

FIGURE 8-3 Parietal cell. A, Electron pho-tomicrograph. B, Schematic. (A, Courtesy of Dr.

Bruce MacKay.)

During the resting state, the cytoplasm ofthe parietal cells is dominated by numeroustubulovesicles. There is also an intracellularcanaliculus that is continuous with the lu-men of the oxyntic gland. The tubulovesiclescontain the enzymes carbonic anhydrase(CA) and H+, potassium (K+)-ATPase (H+,K+-ATPase), necessary for the production andsecretion of acid, on their apical membranes.Thus, in the resting parietal cell, any basalsecretion is directed into the lumen of the tu-bulovesicles and not into the cytoplasm ofthe cell. Stimulation of acid secretion causesthe migration of the tubulovesicles and theirincorporation into the membrane of the can-aliculus as microvilli. As a result, the surfacearea of the canaliculus is greatly expandedto occupy much of the cell. The activities ofthe enzymes, which are now in the canalicu-

lar membrane, increase significantly duringacid secretion. Acid secretion begins within10 minutes of administering a stimulant.This lag time probably is expended in themorphologic conversion and enzyme activa-tions described previously. Following the re-moval of stimulation, the tubulovesicles re-form and the canaliculus regains its restingconfiguration.

The surface epithelial mucous cells are re-cognized primarily by the large number ofmucous granules at their apical surfaces.During secretion, the membranes of thegranules fuse with the cell membrane andexpel mucus.

Peptic cells contain a highly developed en-doplasmic reticulum for the synthesis ofpepsinogen. The proenzyme is packaged in-to zymogen granules by the numerous Golgistructures within the cytoplasm. The zymo-gen granules migrate to the apical surface,where, during secretion, they empty theircontents into the lumen by exocytosis. This

entire procedure of enzyme synthesis, pack-aging, and secretion is discussed in greaterdetail in Chapter 9.

Endocrine cells of the gut also contain nu-merous granules. Unlike in the peptic andmucous cells, however, these hormone-con-taining granules are located at the base of thecell. The hormones are secreted into the in-tercellular space, from which they diffuse in-to the capillaries. The endocrine cells havenumerous microvilli extending from theirapical surface into the lumen. Presumablythe microvilli contain receptors that samplethe luminal contents and trigger hormonesecretion in response to the appropriatestimuli.

Secretion of AcidThe transport processes involved in the secre-tion of HCl are shown in Figure 8-4. The exactbiochemical steps for the production of H+ arenot known, but the reaction can be summar-ized as follows:

FIGURE 8-4 Transport processes in thegastric mucosa accounting for the presenceof the various ions in gastric juice and forthe negative transmembrane potential. C.A.,carbonic anhydrase; Cl−, chloride; CO2, car-

bon dioxide; H+, hydrogen ion; ,bicarbonate; H2O, water; K+, potassium;Na+, sodium; OH−, hydroxyl.

(1)

(2)

H+ is pumped actively into the lumen and

diffuses into the blood, thus givinggastric venous blood a higher pH than thatof arterial blood when the stomach is secret-ing. Step 2 is catalyzed by CA. Inhibition ofthis enzyme decreases the rate but does notprevent acid secretion. Metabolism producesmuch of the carbon dioxide (CO2) used toneutralize hydroxyl (OH–), but at highsecretory rates, CO2 from the blood also is re-quired. The active transport of H+ across themucosal membrane is catalyzed by H+,K+-ATPase, and H+ is pumped into the lumenin exchange for K+. Within the cell, K+ is ac-

cumulated by the sodium (Na+),K+-ATPasein the basolateral membrane. AccumulatedK+ moves down its electrochemical gradientand leaks across both membranes. LuminalK+ is therefore recycled by the H+,K+-ATPase.Chloride (Cl−) enters the cell across thebasolateral membrane in exchange for

. The pumping of H+ out of the cell

allows OH– to accumulate and formfrom CO2, a step catalyzed by CA. The

entering the blood causes theblood’s pH to increase, so the gastric venousblood from the actively secreting stomachhas a higher pH than arterial blood. The pro-duction of OH– is facilitated by the low in-tracellular Na+ concentration established bythe Na+,K+-ATPase. Some Na+ moves downits gradient back into the cell in exchangefor H+, thus further increasing OH– produc-

tion. This process in turn increasesproduction and enhances the driving force

for the entry of Cl− and its uphill movementfrom the blood into the lumen. Thus themovement of Cl− from blood to lumenagainst both electrical and chemical gradi-ents is the result of excess OH– in the cellafter the H+ has been pumped out.

The H+,K+-ATPase catalyzes the pumpingof H+ out of the cytoplasm into the secretorycanaliculus in exchange for K+. The exchangeof H+ for K+ has a 1:1 stoichiometry and istherefore electrically neutral. In the restingcell, the H+,K+-ATPase is found in the mem-branes of the tubulovesicles. As noted previ-ously, following a secretory stimulus, the tu-bulovesicles fuse with the canaliculus, thusgreatly increasing the surface area of thesecretory membrane and the number of“pumps” in it. When acid secretion ends, thetubulovesicles form again, and the can-aliculus shrinks. Although there has beensome controversy over whether the tubu-lovesicles are separate structures or whether

they are collapsed canalicular membrane,current evidence indicates that they are sep-arate structures that fuse with the can-aliculus and undergo recycling following se-cretion. H+,K+-ATPase, like Na+, K+-ATPase,with which it has a 60% amino acid homo-logy, is a member of the P-type ion-trans-porting ATPases, which also include the cal-cium (Ca2+)-ATPase. Inhibition of the H+,K+-ATPase totally blocks gastric acid secretion.Drugs such as omeprazole, a substitutedbenzimidazole, are accumulated in acidspaces and are activated at low pH. Theythen bind irreversibly to sulfhydryl groupsof the H+,K+-ATPase and inactivate the en-zyme. These pump inhibitors are the mostpotent of the different types of acid secretoryinhibitors and are effective agents in thetreatment of peptic ulcer, even ulcer causedby gastrinoma (Zollinger-Ellison syndrome).

Origin of the ElectricalPotential DifferenceThe potential difference across the restingoxyntic gland mucosa is −70 to −80 millivolts(mV) lumen negative with respect to theblood. This charge separation is primarilycaused by the secretion of Cl− (see the previ-ous section) against its electrochemical gradi-ent. This is accomplished by both surface epi-thelial cells and parietal cells. Following thestimulation of acid secretion, the potential dif-ference decreases to −30 or −40 mV becausethe positively charged H+ moves in the samedirection as Cl−. H+ therefore is actuallysecreted down its electrical gradient, therebyfacilitating its transport against a several mil-lionfold concentration gradient.

To produce an electrical gradient and a mil-lionfold concentration gradient of H+, theremust be minimal leakage of ions and acid

back into the mucosa. The ability of thestomach to prevent leakage is attributed tothe so-called gastric mucosal barrier. If thisbarrier is disrupted by aspirin, alcohol, bile,or certain agents that damage the gastric mu-cosa, the potential difference decreases asions leak down their electrochemical gradi-ents. The exact nature of the barrier is un-known; its properties and the consequencesof disrupting it are discussed more fullylater, in the discussion of the patho-physiology of ulcer diseases. The negativepotential difference across the stomach facil-itates acid secretion because H+ is secreteddown the electrical gradient. The potentialdifference can be used to position catheterswithin the digestive tract. With an electrodeplaced at the catheter tip, the oxyntic glandmucosa can be distinguished readily fromthe esophagus (potential difference: −15 mV)or the duodenum (potential difference: −5mV).

Electrolytes of GastricJuiceThe concentrations of the major electrolytes ingastric juice are variable, but they are usuallyrelated to the rate of secretion ( Fig. 8-5). Atlow rates the final juice is essentially a solu-tion of NaCl with small amounts of H+ andK+. As the rate increases, the concentration ofNa+ decreases and that of H+ increases. Theconcentrations of both Cl− and K+ rise slightlyas the secretory rate rises. At peak rates, gast-ric juice is primarily HCl with small amountsof Na+ and K+. At all rates of secretion, theconcentrations of H+, K+, and Cl− are higherthan those in plasma, and the concentration ofNa+ is lower than that in plasma. Thus gastricjuice and plasma are approximately isotonic,regardless of the secretory rate.

FIGURE 8-5 Relationship of the electrolyteconcentrations in gastric juice to the rate ofgastric secretion. Cl−, chloride; H+, hydro-gen ion; K+, potassium; Na+, sodium.

To help understand the changes in ionicconcentration, it is convenient to think ofgastric juice as a mixture of two separate se-cretions: a nonparietal component and aparietal component. The nonparietal com-ponent is a basal alkaline secretion of con-stant and low volume. Its primary constitu-ents are Na+ and Cl−, and it contains K+ at

about the same concentration as in plasma.

In the absence of H+ secretion, can

be detected in gastric juice. The issecreted at a concentration of approximately30 mEq/L. The nonparietal component is al-ways present, and the parietal component issecreted against this background. As the rateof secretion increases, and because the in-crease is caused solely by the parietal com-ponent, the concentrations of electrolytes inthe final juice begin to approach those ofpure parietal cell secretion. Pure parietal cellsecretion is slightly hyperosmotic and con-tains 150 to 160 mEq H+/L and 10 to 20 mEqK+/L. The only anion present is Cl−.

This so-called two-component model ofgastric secretion is an oversimplification.Parietal secretion is modified somewhat bythe exchange of H+ for Na+ as the juice movesup the gland into the lumen. Although suchchanges are minimal, occurring primarily atlow rates of secretion, they do participate in

determining the final ionic composition ofgastric juice.

Knowledge of the composition of gastricjuice is required to treat a patient with chron-ic vomiting or one whose gastric juice is be-ing aspirated and who is being maintainedintravenously. Replacement of only NaCland dextrose results in hypokalemic meta-bolic alkalosis, which can be fatal.

Stimulants of AcidSecretionOnly a few agents directly stimulate the pari-etal cells to secrete acid. The antral hormonegastrin and the parasympathetic mediatoracetylcholine (ACh) are the most importantphysiologic regulators. ACh stimulates gast-rin release in addition to stimulating the pari-etal cell directly.

Evidence has accumulated that an un-known hormone of intestinal origin also stim-ulates acid secretion. This substance tentat-ively has been named entero-oxyntin to denoteboth its origin and its action. In humans, cir-culating amino acids also stimulate the pari-etal cell and provide some of the stimulationof acid secretion that results from the presen-ce of food in the small intestine.

Histamine, which occurs in many tissues(including the entire gastrointestinal [GI]

tract), is a potent stimulator of parietal cellsecretion. Histamine release is regulated bygastrin in most mammals, and it in turnstimulates acid secretion in the sense thatgastrin and ACh do.

Role Of Histamine In AcidSecretionIn 1920 Popielski, a Polish physiologist, dis-covered that histamine stimulated gastricacid secretion. It was then believed by manyinvestigators that gastrin was actuallyhistamine. The confusion cleared somewhatin 1938 when Komarov demonstrated twoseparate secretagogues in the gastric mu-cosa. He showed that trichloroacetic acidprecipitated the peptide gastrin from gastricmucosal extracts, thus leaving histamine inthe supernatant. MacIntosh then suggestedthat histamine was the final common medi-ator of acid secretion. He proposed that gast-rin and ACh released histamine, which in

turn stimulated the parietal cells directly andwas the only direct stimulant of the parietalcells.

At this point it is important to introduceand define the concept of potentiation.Potentiation is said to occur between twostimulants if the response to their simultan-eous administration exceeds the sum of theresponses when each is administered alone.Certain secretory responses in the GI tractdepend on the potentiation of two or moreagonists. In the stomach histamine potenti-ates the effects of gastrin and ACh on theparietal cell. In this way small amounts ofstimuli acting together can often produce anear-maximal secretory response. Potenti-ation requires the presence of separate re-ceptors on the target cell for each stimulantand, in the case of acid secretion, is incom-patible with the final common mediator hy-pothesis.

The first antihistamines discoveredblocked only the histamine H1 receptor,

which mediates actions such as bronchocon-striction and vasodilation. The stimulationof acid secretion by histamine is mediatedby the H2 receptor and is not blocked byconventional antihistamines. The H2 recept-or antagonist cimetidine effectively inhibitshistamine-stimulated acid secretion. Cime-tidine, however, has also been found to in-hibit the secretory responses to gastrin, ACh,and food. Atropine, a specific antagonist ofthe muscarinic actions of ACh, decreases theacid responses to gastrin and histamine aswell as to ACh. When preparations of isol-ated parietal cells (which rule out the pres-ence of stimuli other than those directly ad-ded) are used, investigators have shown thatsome effects of cimetidine on gastrin- andACh-stimulated secretion are caused by in-hibition of the part of the secretory responseresulting from histamine potentiation. Simil-arly, the inhibition of gastrin- and histamine-stimulated secretion by atropine is caused byremoval of the potentiating effects of ACh.

Cimetidine is a more effective inhibitor ofacid secretion than atropine and has fewerside effects. It is an extremely effective drugfor the treatment of duodenal ulcer disease.

Histamine is found in enterochromaffin-like (ECL) cells within the lamina propria ofthe gastric glands. The relationships amonggastrin, histamine, and ACh are shown inFigure 8-6. Located close to the parietal cells,ECL cells release histamine, which acts asa paracrine to stimulate acid secretion. ECLcells have cholecystokinin-2 (CCK-2) recept-ors for gastrin, which stimulate histamine re-lease and synthesis and the growth of theECL cells. ECL cells do not possess ACh re-ceptors. The parietal cell membrane containsreceptors for all three agonists. Parietal cellsexpress histamine H2 receptors, muscarinicM3 receptors, and gastrin/CCK-2 receptors.Although gastrin and ACh play central rolesin the regulation of acid secretion, in the ab-sence of histamine their effects on the pariet-al cell are weak.

FIGURE 8-6 The parietal cell contains re-ceptors for gastrin, acetylcholine (ACh), andhistamine. In addition, gastrin and ACh re-leases histamine from the enterochromaffin-like (ECL) cell. AC, adenylate cyclase; Ca2+,

calcium; cAMP, cyclic adenosine mono-phosphate; H+, hydrogen ion; IP3, inositoltriphosphate; PLC, phospholipase C.

Gastrin and ACh activate phospholipase C(PLC), which catalyzes the formation of inos-itol triphosphate (IP3). IP3 causes the releaseof intracellular Ca2+ and activates calmod-ulin kinases. Histamine activates adenylatecyclase (AC) to form cyclic adenosine mono-phosphate (cAMP), which activates proteinkinase A. Protein kinase A and calmodulinkinases phosphorylate a variety of proteinsto trigger the events leading to secretion andpotentiate each other’s effects. Thus the in-hibition of acid secretion by histamine H2

antagonists, such as cimetidine, results fromboth removal of potentiative interactionswith histamine and inhibition of the stimula-tion caused by histamine released by gastrin.

Stimulation of AcidSecretionThe unstimulated human stomach secretesacid at a rate equal to 10% to 15% of thatpresent during maximal stimulation. Basalacid secretion exhibits a diurnal rhythm withhigher rates in the evening and lower ratesin the morning before awakening. The causeof the diurnal variation is unknown becauseplasma gastrin is relatively constant duringthe interdigestive phase. The stomach emp-tied of food therefore contains a relativelysmall volume of gastric juice, and the pH ofthis fluid is usually less than 2. Thus in the ab-sence of food the gastric mucosa is acidified.

The stimulation of gastric secretion is con-veniently divided into three phases based onthe location of the receptors initiating thesecretory responses. This division is artificial;

shortly after the start of a meal, stimulationis initiated from all three areas at the sametime.

Cephalic PhaseChemoreceptors and mechanoreceptors loc-ated in the tongue and the buccal and nasalcavities are stimulated by tasting, smelling,chewing, and swallowing food. The afferentnerve impulses are relayed through the vag-al nucleus and vagal efferent fibers to thestomach. Even the thought or sight of an ap-petizing meal stimulates gastric secretion.The secretory response to cephalic stimula-tion depends greatly on the nature of themeal. The greatest response occurs to an ap-petizing self-selected meal. A bland mealproduces a much smaller response. The ef-ferent pathway for the cephalic phase is thevagus nerve. The entire response is blockedby vagotomy.

The cephalic phase is best studied by theprocedure known as sham feeding. A dog isprepared with esophageal and gastric fistu-las. When the esophageal fistula is open,swallowed food falls to the exterior withoutentering the stomach. Gastric secretion iscollected from the gastric fistula, and itsvolume and acid content are measured.Stimulation during the cephalic phase rep-resents approximately 30% of the total re-sponse to a meal. The cephalic phase alsocan be studied using a variety of drugs. Hy-poglycemia introduced by tolbutamide orinsulin, or interference with glucose meta-bolism by glucose analogues such as3-methylglucose or 2-deoxyglucose, activ-ates hypothalamic centers that stimulate se-cretion via the vagus nerve.

The vagus nerve acts directly on the pari-etal cells to stimulate acid secretion. It alsoacts on the antral gastrin cells (G cells) tostimulate gastrin release. The mediator at theparietal cells is ACh. The mediator at the

gastrin cell is gastrin-releasing peptide(GRP) or bombesin. Within the antrum,postganglionic vagal neurons release bothstimulatory and inhibitory neurotransmit-ters. Not all of these have been identified,and the overall response is the result of acomplex process. The direct effect on theparietal cell is the more important in humansbecause selective vagotomy of the parietalcell–containing area of the stomach abolishesthe response to sham feeding, whereas an-trectomy only moderately reduces it. Themechanisms involved in the cephalic phaseare illustrated in Figure 8-7.

FIGURE 8-7 Mechanisms stimulatinggastric acid secretion during the cephalicphase. ACh, acetylcholine; G cell, gastrin-producing cell; GRP, gastrin-releasing pep-tide; H+, hydrogen ion.

Gastric PhaseAcid secretion during the gastric phase ac-counts for at least 50% of the response to ameal. When swallowed food first enters thestomach and mixes with the small volumeof juice normally present, buffers (primarilyprotein) contained in the food neutralize theacid. The pH of the gastric contents may riseto 6 or more. Because gastrin release is in-hibited when the antral pH drops below 3and is prevented totally when the pH is lessthan 2, essentially no gastrin is released froma stomach that is void of food. The rise in pHpermits vagal stimulation from the cephalicphase to initiate, and stimuli from the gastricphase to maintain, gastrin release. Increasingthe pH of the gastric contents is not in itselfa stimulus for gastrin release but merely al-lows other stimuli to be effective.

Distention of the stomach and bathing thegastric mucosa with certain chemicals,primarily amino acids, peptides, and

amines, are the effective stimuli of the gastricphase. Distention activates mechanorecept-ors in the mucosa of both the oxyntic and thepyloric gland areas initiating both long ex-tramural reflexes and local, short intramur-al reflexes. All distention reflexes are medi-ated cholinergically and can be blocked byatropine.

Long reflexes also are called vagovagal re-flexes, meaning that both afferent impulsesand efferent impulses are carried by neuronsin the vagus nerve. Mucosal distention re-ceptors send signals by vagal afferents to thevagal nucleus. Efferent signals are sent backto G cells and parietal cells by the vagal ef-ferents.

Short or local reflexes are mediated byneurons that are contained entirely withinthe wall of the stomach. These may be single-neuron reflexes, or they may involve inter-mediary neurons. There are two local dis-tention reflexes. Both are regional reflexes,meaning that the receptor and effector are

located in the same area of the stomach. Dist-ention of a vagally innervated pyloric (an-trum) pouch stimulates gastrin release. Theeffect is decreased, but not abolished, byvagotomy, meaning that the gastrin re-sponse is mediated by both vagovagal re-flexes and local reflexes. This local reflex iscalled a pyloropyloric reflex.

Distention of an antral pouch with pH 1HCl stimulates acid secretion from theoxyntic gland area. Because gastrin releasedoes not take place when the pH is below2, the increase in acid output must be me-diated by a neural reflex. As the discerningreader will have surmised, this vagovagal re-flex is known as a pyloro-oxyntic reflex. Dist-ention reflexes, which are much more effect-ive stimulants of the parietal cell than theyare of the G cell, are illustrated diagrammat-ically in Figure 8-8.

FIGURE 8-8 Mechanisms stimulatinggastric acid secretion during the gastricphase. ACh, acetylcholine; G cell, gastrin-producing cell; H+, hydrogen ion.

Peptides and amino acids stimulate gast-rin release from the G cells. The most potentof these releasers are the aromatic aminoacids. This effect is not blocked by vago-

tomy. Only part of it appears to be blockedby atropine, a finding indicating that proteindigestion products contain chemicals cap-able of directly stimulating the G cell to re-lease gastrin. Acidification of the antral mu-cosa below pH 3 inhibits gastrin release inresponse to digested protein. A few othercommonly ingested substances are also cap-able of stimulating acid secretion. Coffee,both caffeinated and decaffeinated, stimu-lates acid secretion. Ca2+, either in the gastriclumen or as elevated serum concentrations,stimulates gastrin release and acid secretion.Considerable debate exists about the effectsof alcohol on gastric secretion. Alcohol hasbeen shown to stimulate gastrin release andacid secretion in some species; however,these effects do not seem to occur in humans.

Release Of GastrinConsiderable evidence has accumulated fa-voring the mechanism in Figure 8-9 to ex-

plain the regulation of gastrin release. GRPacts on the G cell to stimulate gastrin release,and somatostatin acts on the G cell to inhibitrelease. GRP is a neurocrine released by vag-al stimulation. This explains why atropinedoes not block vagally mediated gastrin re-lease. Somatostatin acts as a paracrine, andits release is inhibited by vagal stimulation.In the isolated, perfused rat stomach, vagalstimulation increases GRP release and de-creases somatostatin release into the perfus-ate. Thus vagal activation stimulates gastrinrelease by releasing GRP and inhibiting therelease of somatostatin. Evidence also indic-ates that gastrin itself increases somatostatinrelease in a negative feedback manner.

FIGURE 8-9 Mechanism for the regulationof gastrin release. ACh, acetylcholine; GRP,

gastrin-releasing peptide; H+, hydrogen ion;SS, somatostatin.

Acid in the lumen of the stomach is be-lieved to act directly on the somatostatin cellto stimulate the release of somatostatin,thereby preventing gastrin release. Proteindigestion products—peptides, amino acids,and amines—may act directly on the G cell(or be absorbed by the G cell) to stimulategastrin release. These substances most likelybind to receptors located on the apical mem-brane of the G cells, which are in contactwith the gastric lumen.

Data indicate that atropine can block somegastrin release stimulated by protein diges-tion products. This is evidence that luminalreceptors may be activated, resulting in acholinergic reflex that leads to gastrin re-lease. There is also evidence that this reflexmay operate by releasing GRP and inhibitingsomatostatin release.

Intestinal PhaseProtein digestion products in the duodenumstimulate acid secretion from denervatedgastric mucosa, a finding indicating the pres-ence of a hormonal mechanism. In humans,the proximal duodenum is rich in gastrin,which has been shown to contribute to theserum gastrin response to a meal. In dogs,liver extract releases a hormone from theduodenal mucosa that stimulates acid secre-tion without increasing serum gastrin levels.This hormone tentatively has been namedentero-oxyntin. Its significance in humans isunknown.

Intravenous infusion of amino acids alsostimulates acid secretion. Therefore a goodportion of the stimulation attributed to theintestinal phase may be caused by absorbedamino acids. Intestinal stimuli result in onlyapproximately 5% of the acid response toa meal. The gastric phase is responsible formost acid secretion.

Figure 8-10 summarizes the mechanismsand final stimulants acting in all threephases.

FIGURE 8-10 Mechanisms for stimulatingacid secretion. ACh, acetylcholine; ECL cell,enterochromaffin-like cell; G cell, gastrin-producing cell; GRP, gastrin-releasing pep-tide.

Inhibition of AcidSecretionWhen food first enters the stomach, its buffersneutralize the small volume of gastric acidpresent during the interdigestive phase. Asthe pH of the antral mucosa rises above 3,gastrin is released by the stimuli of the ceph-alic and gastric phases. One hour after themeal, the rate of gastric secretion is maximal,the buffering capacity of the meal is saturated,a significant portion of the meal has emptiedfrom the stomach, and the acid concentrationof the gastric contents increases. As the pHfalls, gastrin release is inhibited, removing asignificant factor for the stimulation of gastricacid secretion. This passive negative feedbackmechanism is extremely important in the reg-ulation of acid secretion. In addition, soma-tostatin released by the drop in intragastricpH also directly inhibits the parietal cells and

inhibits the release of histamine from theECL cells. The relationship between the rateof acid secretion and the pH and volume ofthe gastric contents is shown in Figure 8-11.

FIGURE 8-11 The relationship betweengastric secretory rate, intragastric pH, andvolume of gastric contents during a meal.(From Johnson LE: Essential Medical Physiology, 3rd ed.

Philadelphia, Academic Press, 2003.)

Evidence exists for several hormonalmechanisms for the inhibition of gastric acidsecretion. These hormones are released fromduodenal mucosa by acid, fatty acids, orhyperosmotic solutions and collectively aretermed enterogastrones. They often inhibitgastric emptying as well as acid secretion.Teleologically these mechanisms ensure thatthe gastric contents are delivered to the smallbowel at a rate that does not exceed the capa-city for digestion and absorption. They alsoprevent damage to the duodenal mucosathat can result from acidic and hyperosmoticsolutions.

Gastric inhibitory peptide (GIP) is re-leased by fatty acids and acts at the parietalcell to inhibit acid secretion. Secretin mayalso be classified as an enterogastrone be-cause it inhibits gastric acid secretion. Theimportance and physiologic significance ofthese effects in humans have not been de-termined. Cholecystokinin (CCK) is aphysiologically significant inhibitor of gast-

ric emptying. Hyperosmotic solutions re-lease an as yet unidentified enterogastrone.Strong evidence also exists that acid initiatesa nervous reflex from receptors in the duo-denal mucosa that suppresses acid secretion.These mechanisms are summarized in Fig-ure 8-12.

FIGURE 8-12 Mechanisms for inhibitingacid secretion. GIP, gastric inhibitory pep-tide.

PepsinPepsinogen has a molecular weight of 42,500and is split to form the active enzyme pepsin,which has a molecular weight of 35,000.Pepsinogen is converted to pepsin in the gast-ric juice when the pH drops below 5. Pepsinitself can catalyze the formation of additionalpepsin from pepsinogen. Pepsin begins thedigestion of protein by splitting interior pep-tide linkages (see Chapter 11).

Pepsinogens belong to two main groups: Iand II. The pepsinogens in the first group aresecreted by peptic and mucous cells of theoxyntic glands; those in the second group aresecreted by mucous cells present in the pylor-ic gland area and duodenum, as well as inthe oxyntic gland area. Pepsinogens appearin the blood, and considerable evidence indic-ates that their levels may be correlated withduodenal ulcer formation. This is discussed

later in this chapter in connection with pep-tic ulcer disease.

The strongest stimulant of pepsinogen se-cretion is ACh. Thus vagal activation duringboth the cephalic and the gastric phases res-ults in a significant proportion of the totalpepsinogen secreted. H+ plays an importantrole in several areas of pepsin physiology.First, acid is necessary to convert pepsinogento the active enzyme pepsin. At pH 2 thisconversion is almost instantaneous. Second,acid triggers a local cholinergic reflex thatstimulates the chief cells to secrete. Thismechanism is atropine sensitive and may ac-count in part for the strong correlationbetween acid and pepsin outputs. Third, theacid-sensitive reflex greatly enhances the ef-fects of other stimuli on the peptic cell. Thismechanism ensures that large amounts ofpepsinogen are not secreted unless sufficientacid for conversion to pepsin is present.Fourth, acid releases the hormone secretinfrom duodenal mucosa. Secretin also stim-

ulates pepsinogen secretion, although it isquestionable whether enough secretin ispresent to do so under normal conditions.

The hormone gastrin is usually listed asa pepsigogue. The infusion of gastrin in-creases pepsin secretion. In dogs, the entireresponse can be accounted for by the stim-ulation of acid secretion by gastrin and thesubsequent activation of the acid-sensitivereflex mechanism for pepsinogen secretion.In humans, gastrin may be a weak pep-sigogue in its own right. The mechanismsregulating pepsinogen secretion are sum-marized in Figure 8-13.

FIGURE 8-13 Summary of mechanismsfor stimulating pepsinogen secretion and ac-tivation to pepsin. ACh, acetylcholine; Gcell, gastrin-producing cell; H+, hydrogenion.

Pepsin plays an important role in the ul-ceration of the stomach and duodenum,hence the term peptic ulcer. In the absence ofpepsin, gastric acid does not produce an ul-

cer. Thus one of the benefits of the inhibitionof acid secretion or neutralization of gastricacid during ulcer therapy may be the elimin-ation of pepsin.

MucusVagal nerve stimulation and ACh increasesoluble mucus secretion from the mucousneck cells. Soluble mucus consists of mu-coproteins and mixes with the gastric chymelubricating it.

Surface mucous cells secrete visible or in-soluble mucus in response to chemical stimu-lants (e.g., ethanol) and in response to phys-ical contact and friction with roughage in thediet. Visible mucus is secreted as a gel thatentraps the alkaline component of the surfacecell secretion. It is present during the interdi-gestive phase and protects the mucosa withan alkaline layer of lubricant. A portion of thiscoating is made up of mucus-containing sur-face cells that have been shed and trapped inthe layer of mucus. During the response toa meal, insoluble mucus protects the mucosafrom physical and chemical damage. It neut-ralizes a certain amount of acid and prevents

pepsin from coming into contact with themucosa. On contact with acid, insoluble mu-cus precipitates into clumps and passes intothe duodenum with the chyme.

Intrinsic FactorIntrinsic factor is a mucoprotein with a mo-lecular weight of 55,000 that is secreted bythe parietal cells. It combines with vitamin B12

to form a complex that is necessary for theabsorption of this vitamin by the ileal mu-cosa. Failure to secrete intrinsic factor is as-sociated with achlorhydria and with the ab-sence of parietal cells, which results in vit-amin B12 deficiency or pernicious anemia. Thedevelopment of this disease is poorly under-stood because the liver stores enough vitaminB12 to last several years. The condition istherefore not recognized until long after thechanges have taken place in the gastric mu-cosa.

Growth of the MucosaThe growth of the GI mucosa is influenced bynon-GI hormones and factors associated withthe ingestion and digestion of a meal, suchas GI hormones, nervous stimulation, secre-tions, and trophic substances present in thediet. Hypophysectomy results in atrophy ofthe digestive tract mucosa and the pancreas.The effects of hypophysectomy on growth canbe prevented by administration of growthhormone. When administered to hypophysec-tomized rats, gastrin prevents atrophy of theGI mucosa and exocrine pancreas but doesnot affect the growth of other tissues. Inter-esting evidence indicates that adrenocorticalsteroids may trigger early postnatal develop-ment of the GI tract.

Gastrin is an important and necessary reg-ulator of the growth of the oxyntic gland mu-cosa. It also stimulates growth of the intestinaland colonic mucosa and the exocrine pan-

creas. In humans, antrectomy causes atrophyof the remaining gastric mucosa; in rats, itcauses atrophy of all GI mucosa (except thatof the antrum and esophagus) and the exo-crine pancreas. These changes are preventedby administration of exogenous gastrin.Hypergastrinemia results primarily in an in-crease in parietal and ECL cells. Gastrin isa potent stimulator of ECL cell proliferationvia the CCK-2 receptor, and prolonged hy-pergastrinemia leads to ECL cell hyper-plasia. Disruption of gastrin gene expressionin mice inhibits parietal cell maturation anddecreases their number. Conversely, overex-pression of the gene results in increased pro-liferation of the gastric epithelium, increasednumber of parietal cells, and increased acidsecretion.

Partial resection of the small intestine fortumor removal or for a variety of other reas-ons (e.g., treatment of morbid obesity) res-ults in adaptation of the remaining mucosa.The mucosa of the entire digestive tract un-

dergoes hyperplasia, which increases itsability to digest and transport nutrients or, inthe case of the stomach, to secrete acid. Re-section increases gastrin levels but not suffi-ciently to account for the adaptive changes.Evidence indicates that increased exposureof the mucosa to luminal contents plays animportant role. After removal of proximalintestine, the distal intact mucosa is exposedto an increased load of pancreatic juice, bile,and nutrients. Investigators have hypothes-ized that bile and pancreatic juice containgrowth factors that stimulate the adaptiveresponse. The growth factors have not beenisolated and tested. Increased uptake of nu-trients by the distal mucosa has also been hy-pothesized to result in growth. The effects ofspecific nutrients have not been proved, andinvestigators disagree on whether growth iscaused by an increased workload or an in-crease in the available supply of calories.Good evidence exists that a hormone differ-ent from gastrin also is involved in the ad-

aptive response. This may be one of theglucagon-like peptides released from thedistal small intestine.

The diet also contains polyamines that arerequired for growth. Trophic agents such asgastrin stimulate polyamine synthesis in theproliferative cells. Thus increased luminalpolyamines from the diet, coupled with syn-thesis stimulated by trophic hormones, mayexplain some of the regulation of mucosalgrowth triggered by changes in the diet.

CLINICALAPPLICATIONSGastric and duodenal ulcers arelumped together under the head-ing of peptic ulcer disease. Al-though the formation of bothtypes of ulcers requires acid andpepsin, their causes are basicallydifferent. Quite simply, an ulcerforms when damage from acidand pepsin overcomes the ability

of the mucosa to protect itselfand replace damaged cells. In thecase of gastric ulcer, the defect ismore often in the ability of themucosa to withstand injury. Inthe case of duodenal ulcer, goodevidence indicates that the mu-cosa is exposed to increasedamounts of acid and pepsin. Thisanalysis is an oversimplificationbecause both factors are nodoubt important in all cases ofulcer.

Representative acid secretoryrates for normal individuals andfor patients with gastrointestinaldisorders are shown in Table 8-1.Maximal acid secretory outputsometimes is measured but in it-self is of little value in diagnosingulcer disease. Normal subjectssecrete approximately 25 mEq

hydrogen (H+)/hour, in responseto maximal injection of histam-ine, betazole, or gastrin. Themean output of patients withduodenal ulcer disease is ap-proximately 40 mEq H+/hour, butthe degree of overlap among in-dividuals is so great as to renderthe determination useless in dia-gnosis. The highest rates of acidsecretion are seen in cases ofgastrinoma (Zollinger-Ellisonsyndrome), but again individualoverlap makes it impossible todifferentiate between this condi-tion and duodenal ulcer on thebasis of secretory data alone.Lower than normal secretoryrates are found in cases of gastriculcer, and still lower secretoryrates are found in patients withgastric carcinoma. Many patients

in the latter two groups,however, fall well within thenormal range.

TABLE 8-1Comparison of Acid OutputValues from the Human Stom-ach ∗∗

∗Basal acid output occurs at rest, andmaximal acid output occurs during stim-ulation with histamine. The value is de-termined by multiplying the hourlyvolume of gastric juice aspirated timesthe hydrogen ion concentration of thejuice.

Because of the feedback mech-anism whereby antral acidifica-

tion inhibits gastrin release, thegeneral statement can be madethat serum gastrin levels are re-lated inversely to acid secretorycapacity. Patients with gastric ul-cer and carcinoma usually havehigher than normal serum gast-rin levels. Serum gastrin levels inpernicious anemia actually mayapproach those seen in gast-rinoma. Obviously, patients withgastrinoma are an exception tothis rule because their hypergast-rinemia is derived not from theantrum but from a tumor notsubject to inhibition by gastricacid. Except for the special testsmentioned in Chapter 1, serumgastrin levels cannot be used todifferentiate various secretoryabnormalities.

The decreased rate of acid se-cretion experienced with gastriculcer is caused in part by the fail-ure to recover acid that has beensecreted and then has leakedback across the damaged gastricmucosa. The concept of the gast-ric mucosal barrier is illustratedin Figure 8-14. The normal gast-ric mucosa is relatively imperme-able to H+. When the gastric mu-cosal barrier is weakened ordamaged, H+ leaks into the mu-cosa in exchange for sodium(Na+). As H+ accumulates in themucosa, intracellular buffers aresaturated, and the intracellularpH decreases, thus resulting ininjury and cell death. Potassium(K+) leaks from the damagedcells into the lumen. H+ damagesmucosal mast cells. They then re-

lease histamine, which exacer-bates the condition by acting onH1 receptors in the mucosal ca-pillaries. The results are localischemia, hypoxia, and vascularstasis. Plasma proteins and pep-sin leak into the gastric juice; ifdamage is severe, bleeding willoccur. Common agents that pro-duce mucosal damage of thistype are aspirin, ethanol, and bilesalts. The mucosal lesions pro-duced by topical damage to thegastric barrier may be forerun-ners of gastric ulcer.

FIGURE 8-14 Events that fol-low damage to the gastric mu-cosal barrier. H+, hydrogen ion;K+, potassium; Na+, sodium.

The exact nature of the barrieris unknown. It is probablyphysiologic as well as anatomic.Cell membranes and junctionalcomplexes prevent normal back-diffusion of H+. Diffused H+ nor-mally is transported actively

back into the lumen. Factors thathave been speculated to play arole in maintaining mucosal res-istance are blood flow, mucus,bicarbonate secretion, cellular re-newal, and chemical factors suchas gastrin, prostaglandins, andepidermal growth factor. Thelast three agents have all beenshown to decrease the severityand promote the healing of gast-ric ulcers.

Factors that have been elucid-ated as important in duodenalulcer formation pertain to acidand pepsin secretion. Patientswith duodenal ulcer have on theaverage 2 billion parietal cellsand can secrete approximately 40mEq H+/hour. Comparable meas-urements for normal individualsare approximately 50% of this

number. In addition, the secre-tion of pepsin is doubled in theduodenal ulcer group, as can bedetected by measuring plasmapepsinogen. Although fastingserum gastrin is normal in pa-tients with duodenal ulcer, thegastrin response to a meal andsensitivity to gastrin are in-creased. Increased serum gastrinafter a meal is caused in part bythe fact that acid suppressesgastrin release less effectively inpatients with duodenal ulcerthan in controls. The increasedparietal cell mass may thereforebe caused by the trophic effect ofgastrin.

The major acquired factor inthe origin of both gastric ulcerand duodenal ulcer is the bacteri-um Helicobacter pylori. The infec-

tion is found in 80% of patientswith duodenal ulcer and virtu-ally 100% of patients with gastriculcers whose ulcers were notcaused by the long-term use ofaspirin or other nonsteroidalanti-inflammatory drugs(NSAIDs). H. pylori is a gram-negative bacterium, character-ized by high urease activity,which metabolizes urea into am-monia to neutralize gastric acid.This reaction allows the bacteri-um to withstand the acid envir-onment of the stomach and tocolonize the mucosa. The result-ing production of ammonium(NH4

+) is believed to be a majorcause of cytotoxicity becauseNH4

+ directly damages epithelialcells and increases the permeab-ility of the mucosa (i.e., it “breaks

the mucosal barrier”). The bac-teria produce numerous otherfactors, such as platelet-activat-ing factor and cytokines, thatalso damage cells. All thesefactors probably contribute togastric ulcer formation. H. pyloriinfection can progress from gast-ritis to gastric cancer.

NSAIDs inhibit the enzymecyclooxygenase, thereby redu-cing the synthesis ofprostaglandins (PGE2 and PGI2)from arachidonic acid. Theprostaglandins are normally pro-tective, and the increasedarachidonic acid results in theproduction of leukotriene B4

(LTB4) and subsequent neutro-phil adhesion to the walls of mu-cosal capillaries. This process

leads to ischemia and mucosaldamage.

H. pylori also causes the in-creased acid secretion associatedwith duodenal ulcer. Comparedwith normal individuals, pa-tients with duodenal ulcer haveincreased basal acid output, in-creased gastrin-releasing peptide(GRP)-stimulated acid output,increased maximal acid outputin response to gastrin, increasedratio of basal acid output togastrin-stimulated maximal acidoutput, and increased ratio ofGRP-stimulated maximal acidoutput to gastrin-stimulatedmaximal acid output. All thesefindings, except the increasedmaximal acid output in responseto gastrin, totally disappearedfollowing eradication of the H.

pylori infection. The increasedacid secretory and serum gastrinresponses to GRP appear to berelated to a decreased inhibitionof gastrin release and parietalcell secretion by somatostatin inH. pylori–infected persons. Pat-terns of H. pylori–related gastritisdiffer in gastric and duodenal ul-cer. Gastric ulcers are associatedwith diffuse gastritis, whereasduodenal ulcers are associatedpredominantly with the infectionof the antrum. Although all themechanisms by which H. pyloriaffects the mucosa have not beenelucidated, the informationavailable coincides with theknown pathophysiology of bothgastric and duodenal ulcer dis-eases.

Medical treatment of duodenalulcer disease usually consists ofadministering antacids to neut-ralize secreted acid or a histam-ine H2-receptor blocker to inhibitsecretion. The H+,K+-ATPase(proton pump) inhibitoromeprazole blocks all acid secre-tion. It is extremely effective intreating duodenal ulcers, eventhose caused by gastrinoma. Sur-gical treatment is based entirelyon physiology. The most com-monly used operations are vago-tomy and antrectomy. These pro-cedures result in a 60% to 70%decrease in acid secretion by re-moving one or both major stim-ulants of acid secretion. With theadvent of the H2 blockers andproton pump inhibitors, ulcersare now rarely treated by surgic-

al intervention. To prevent recur-rence, physicians eradicate H.pylori. This is best done by givingantibiotics in combination withomeprazole, which increases thesusceptibility of the bacteria toantibiotic treatment.

Summary1. The functions of gastric juice are attributedto acid, pepsin, intrinsic factor, mucus, andwater.2. Acid is secreted in concentrations as highas 150 mEq/L at high rates of secretion; theacid converts inactive pepsinogen to the act-ive enzyme pepsin, kills bacteria, and solubil-izes some foodstuffs.3. Acid is secreted by the parietal cells, whichcontain the enzyme H+,K+-ATPase on their ap-ical secretory membranes.4. The concentrations of the electrolytes ingastric juice vary with the rate of secretion.5. The three major stimulants of acid secretionare the hormone gastrin, the cholinergic neur-omediator ACh, and the paracrine histamine,which is released from ECL cells in responseto gastrin.6. During the cephalic phase of secretion, vag-al activation stimulates the parietal cells dir-

ectly via ACh and releases gastrin from theG cells via GRP.7. During the gastric phase of secretion, dis-tention of the wall of the stomach stimulatesthe parietal cells and releases gastrin viaboth mucosal and vagovagal reflexes; pro-tein digestion products stimulate the G cellsdirectly to release gastrin.8. When the pH of luminal contents dropsbelow 3, somatostatin is released from Dcells in the antrum and oxyntic gland area,where it inhibits gastrin release, histaminerelease from ECL cells, and acid secretion.9. Acid secretion is inhibited further whenchyme enters the duodenum, triggers the re-lease of inhibitory hormones, and initiatesinhibitory neural reflexes.10. Pepsinogen secretion is stimulated byvagal activation and ACh and by acid in thelumen of the stomach.11. Intrinsic factor, secreted by the parietalcells, is required for the absorption of vitam-

in B12 by a specific carrier mechanism locatedin the ileum.

KEY WORDS ANDCONCEPTSIntrinsic factorHydrogen ionPepsinMucusWaterGastric mucosal barrierOxyntic gland areaPyloric gland areaAntrumParietal cellsPeptic/chief cellsPepsinogenTubulovesiclesIntracellular canaliculusCarbonic anhydraseH+,K+-ATPaseHistaminePotentiation

CimetidineEnterochromaffin-like cellsGastrin-releasing peptide/bombesinVagovagal reflexesSomatostatinEnterogastronesGastric inhibitory peptideSecretinCholecystokinin

Suggested ReadingsBeaumont, W. Experiments and Observations on the

Gastric Juice and the Physiology of Digestion. NewYork: Dover; 1955.

Chan, F. K., Leung, W. K. Peptic ulcer disease. Lancet.2002; 360:933–940.

El-Omar, E. M., Penman, I. D., Ardill, J. E. S., et al.Helicobacter pylori infection and abnormalities of

acid secretion in patients with duodenal ulcer dis-ease. Gastroenterology. 1995; 109:681–691.

Feldman, M., Richardson, C. T., Gastric acid secre-tion in humansJohnson, L. R., eds. Physiology ofthe Gastrointestinal Tract, vol 1. New York:Raven Press, 1981.

Okamot, C., Karvar, S., Forte, J. G., Yao, X., The cellbiology of gastric acid secretionJohnson, L. R.,eds. Physiology of the Gastrointestinal Tract, ed 5,vol 2. San Diego: Elsevier, 2012.

Hersey, S. J., Gastric secretion of pepsinogensJohn-son, L. R., eds. Physiology of the GastrointestinalTract, ed 3, vol 2. New York: Raven Press, 1994.

Johnson, L. R., McCormack, S. A., Regulation ofgastrointestinal growthJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 3, vol1. New York: Raven Press, 1994.

Lindström, E., Chen, D., Norlen, P., et al. Control ofgastric acid secretion: the gastrin–ECLcell–parietal cell axis. Comp Biochem Physiol A MolIntegr Physiol. 2001; 128:505–514.

Modlin, I. M., Sachs, G. Acid Related Diseases. Milan:Schnetztor-Verlag Gmbh D-Konstanz; 1998.

Polk, D. B., Frey, M. R., Mucosal restitution and re-pairJohnson, L. R., eds. Physiology of the

Gastrointestinal Tract, ed 5, vol 1. San Diego, El-sevier, 2012.

Schubert, M. L., Regulation of gastric acid secre-tionJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 2. San Diego: El-sevier, 2012.

Silen, W., Gastric mucosal defense and repairJohn-son, L. R., eds. Physiology of the GastrointestinalTract, ed 2, vol 2. New York: Raven Press, 1987.

Pancreatic Secretion

Object ives

Describe the two components of pancreaticexocrine secretion, their cells of origin, andtheir functions.Understand the mechanisms involved inthe formation of both the electrolyte(aqueous) and enzymatic components ofpancreatic secretion.Explain the hormonal and neural regulationof both the aqueous and enzymatic com-ponents of pancreatic secretion.

Discuss the cellular basis for potentiationand its importance in the pancreatic re-sponse to a meal.Discuss the various clinical conditions res-ulting from the decreased production ofeither or both the aqueous and enzymaticcomponents of pancreatic juice.Understand how the preceding clinicalconditions may arise.

Pancreatic exocrine secretion is divided con-veniently into an aqueous or bicarbonate (

) component and an enzymatic com-ponent. The function of the aqueous com-ponent is the neutralization of the duodenalcontents. As such, it prevents damage to theduodenal mucosa by acid and pepsin andbrings the pH of the contents into the op-timal range for activity of the pancreatic en-zymes. The enzymatic or protein compon-

ent is a low-volume secretion containing en-zymes for the digestion of all normal con-stituents of a meal. Unlike the enzymessecreted by the stomach and salivary glands,the pancreatic enzymes are essential to nor-mal digestion and absorption.

Functional AnatomyThe exocrine pancreas can best be likened toa cluster of grapes, and its functional unitsresemble the salivons of the salivary glands.Groups of acini form lobules separated byareolar tissue. Each acinus is formed fromseveral pyramidal acinar cells oriented withtheir apices toward the lumen. The lumen ofthe spherical acinus is drained by a ductulewhose epithelium extends into the acinus inthe form of centroacinar cells. Ductules join toform intralobular ducts, which in turn draininto interlobular ducts. These join the majorpancreatic duct draining the gland.

The acinar cells secrete a small volume ofjuice rich in protein. Essentially all the pro-teins present in pancreatic juice are digestiveenzymes. Ductule cells and centroacinarcells produce a large volume of watery secre-

tion containing sodium (Na+) and asits major constituents.

Distributed throughout the pancreaticparenchyma are the islets of Langerhans orthe endocrine pancreas. The islets produceinsulin from the beta cells and glucagonfrom the alpha cells. In addition, the pan-creas produces the candidate hormone pan-creatic polypeptide and contains largeamounts of somatostatin, which may act as aparacrine to inhibit the release of insulin andglucagon.

The efferent nerve supply to the pancreasincludes both sympathetic and parasym-pathetic nerves. Sympathetic postganglionicfibers emanate from the celiac and superiormesenteric plexuses and accompany the ar-teries to the organ. Parasympathetic pregan-glionic fibers are distributed by branches ofthe vagi coursing down the antral-duodenalregion. Hence, surgical vagotomy for pepticulcer disease affects not only the intended

target organ, the hypersecreting stomach,but also the pancreas. More recently, moreselective operations have been designed toresect only the vagal branches passing to thestomach. Vagal fibers terminate either atacini and islets or at the intrinsic cholinergicnerves of the pancreas. In general, the sym-pathetic nerves inhibit, and the parasym-pathetic nerves stimulate, pancreatic exo-crine secretion.

Mechanisms of Fluid andElectrolyte SecretionThe pancreas secretes approximately 1 L offluid per day. At all rates of secretion, pancre-atic juice is essentially isotonic with extracel-lular fluid. At low rates the primary ions areNa+ and chloride (Cl−). At high rates Na+ and

predominate. Potassium ions (K+)are present at all rates of secretion at a concen-tration equal to their concentration in plasma.The concentrations of Na+ in pancreatic juiceand in plasma also are approximately equal.

The aqueous component is secreted by theductule and centroacinar cells and may con-tain 120 to 140 milliequivalents (mEq) of

/L, several times its concentration inplasma. The electropotential difference acrossthe ductule epithelium is 5 to 9 millivolts

(mV), lumen negative. Hence is

secreted against both electrical and chemicalgradients. This is often considered evidence

that is transported actively acrossthe luminal surface of the cells. Although theexact mechanism involved in pancreatic

secretion is unknown, the currentmodel is shown in Figure 9-1. This model isbased on information that shows the follow-

ing: (1) more than 90% of in pancre-atic juice is derived from plasma; (2) the se-

cretion of occurs against an electro-chemical gradient and is an active process;

(3) secretion is blocked by ouabain,meaning that Na+,K+-adenosine triphos-

phatase (ATPase) is involved; (4) se-cretion involves Na+-hydrogen ion (H+) and

Cl−- exchangers and carbonic an-

hydrase; and (5) secretion is de-creased significantly in the absence of extra-

cellular Cl−. In Figure 9-1, most of the

enters the cell across the basolateralmembrane cotransported with Na+ . Intracel-

lular is also produced by the diffu-sion of carbon dioxide (CO2) into the cell, itshydration by carbonic anhydrase, and disso-

ciation into H+ and . The H+ is trans-ported across the basolateral membrane bythe Na+-H+ exchanger. Both these steps de-pend on the Na+ gradient established byNa+,K+-ATPase. When H+ reaches the

plasma, it combines with to pro-duce additional CO2. In some species such

as the rat, enters the lumen in ex-change for Cl−.

FIGURE 9-1 Model for the secretion of bi-

carbonate ( ) by the pancreaticduct cell. Cl−, chloride; CO2, carbon dioxide;H+, hydrogen ion; H2O, water; K+, potassi-um; Na+, sodium.

In humans and other species able to

secrete in concentrations up to 140

mEq/L, enters through a channelthat is also able to secrete Cl−. The rate of

secretion depends on the availabil-ity of luminal Cl−, which is dependent on theopening of this channel in the apical mem-brane. This channel, which is the cysticfibrosis transmembrane conductance regu-lator (CFTR), is activated by cyclic adenosinemonophosphate (cAMP) in response to stim-ulation by secretin and is present in ductcells but not acinar cells. Na+ moves para-cellularly down the established electrochem-ical gradient from the plasma to the lumen

of the gland. Water passively moves fromthe plasma into the lumen, down the osmoticgradient created by the secretion of Na+ and

. Most water moves throughaquaporin 1 channels in both the basolateraland apical membranes. This secretion is sim-ilar to that occurring in the parietal cells of

the stomach, except that the H+ andare transported in opposite directions. Thusthe venous blood from an actively secretingpancreas has a lower pH than that from aninactive gland.

As in gastric juice, the ionic concentrationsin pancreatic juice vary with the rate of se-cretion ( Fig. 9-2). The concentrations of an-

ions (Cl− and ) in pancreatic juice arerelated inversely to each other, as are theconcentrations of cations (Na+ and H+) ingastric juice. Because these relationships areanalogous, it may be surmised that analog-

ous theories have been proposed to explainthem:

FIGURE 9-2 Relationship between therate of secretion of pancreatic juice and theconcentrations of its major ions. Cl−, chlor-

ide; , bicarbonate; K+, potassium;Na+, sodium.

The two-component hypothesis assumesthat one cell type, the acinar cell, secretes

a small amount of fluid whose major ionsare Na+ and Cl−. The duct cells secrete large

volumes of juice rich in Na+ andin response to stimulation. At low rates ofsecretion, the Cl− concentration of the juiceis therefore relatively high. As the secretoryrate increases, the fixed amount of Cl− beingsecreted is diluted by the much larger

volume of -containing juice, and thefinal concentrations of the two anions ap-

proach those in the pure secretion.Another theory proposes that the cells

primarily secrete and that, as itmoves down the ducts, it is exchanged forCl−. At low rates of secretion, there is suffi-cient time for the exchange to be nearly com-plete, and the concentration of each anionis equal to its concentration in plasma. Asthe rate of secretion increases, less time isavailable for exchange, and the final ionicmakeup of pancreatic juice approaches that

of the originally secreted solution containing

only and Na+.Both processes probably are involved in

determining the final composition of thesecreted juice.

Mechanisms of EnzymeSecretionThe exocrine pancreas has the highest dailyrate of protein synthesis of any organ in thebody. A liter of pancreatic juice may contain10 to 100 g of protein that enters the intestineeach day. The pancreatic acinar cells synthes-ize and secrete major enzymes for the diges-tion of all three primary foodstuffs. Like pep-sin, the pancreatic proteases are secreted asinactive enzyme precursors and are conver-ted to active forms in the lumen. Pancreaticamylase and lipase are secreted in activeforms. The activation and specific actions ofthe pancreatic enzymes are covered in detailin Chapter 11.

Although a certain amount of controversyexists concerning the mechanisms of the syn-thesis and secretion of enzymes by the acinarcells, the process outlined in Figure 9-3 is ac-

cepted by most authorities. The secretoryprocess begins with the synthesis of export-able proteins in association with polysomesattached to the cisternae of the rough endo-plasmic reticulum (RER) (step 1). As it is be-ing synthesized, the elongating protein, dir-ected by a leader sequence of hydrophobicamino acids, enters the cisternal cavity,where it is collected after synthesis is com-plete (step 2).

FIGURE 9-3 Pancreatic acinar cell. Notethe major steps in the cellular synthesis andsecretion of enzymes, and see the text foran explanation of steps 1 through 6. RER,rough endoplasmic reticulum.

Once within the cisternal space, enzymesremain membrane bound until they aresecreted from the cell. The enzymes next

move through the cisternae of the RER totransitional elements, which are associatedwith smooth vesicles at the Golgi periphery.Possibly as a result of pinching off the trans-itional elements containing them, the en-zymes become associated with the Golgi ves-icles (step 3), which transport them to con-densing vacuoles (step 4). Energy is requiredfor transport through the endoplasmic retic-ulum and Golgi vesicles to the condensingvacuoles. Within the condensing vacuoles,the enzymes are concentrated to form zymo-gen granules (step 5). They are then storedin the zymogen granules that collect at theapex of the cell. After a secretory stimulus,the membrane of the zymogen granule fuseswith the cell membrane, thus ultimately rup-turing and expelling the enzymes into the lu-men (step 6). This is the only step in the pro-cess that requires a secretory stimulus. Thehuman acinar cell does not have cholecys-tokinin 1 (CCK1) receptors, so CCK does notstimulate secretion directly. CCK activates

cholinergic reflexes via CCK1 receptors, andacetylcholine (Ach) activates muscarinic re-ceptors on the acinar cell. The results are arelease of calcium (Ca2+) from the endoplas-mic reticulum and the subsequent activationof protein kinases, which stimulate exocytos-is.

Regulation of SecretionAs may be expected from its function to neut-ralize the duodenum, the secretion of fluid

and (the aqueous component) islargely determined by the amount of acid en-tering the duodenum. The secretion of pan-creatic enzymes is similarly determinedprimarily by the amount of fat and protein en-tering the duodenum. Control of pancreaticsecretion is regulated primarily by secretin,CCK, and vagovagal reflexes. Intestinal stim-uli account for most pancreatic secretion, butsecretion is also stimulated during the cephal-ic and gastric phases.

Basal pancreatic secretion in humans is lowand difficult to measure. The basal secretion

of is 2% to 3% of maximal, and basalenzyme secretion is 10% to 15% of maximal.The stimuli for basal secretion are unknown.Because the isolated perfused pancreas

secretes basally, this secretion may be an in-trinsic property of the gland.

Cephalic PhaseTruncal vagotomy reduces the pancreaticsecretory response to a meal by approxim-ately 60%. Most of this decrease is causedby the interruption of vagovagal reflexes andthe removal of the potentiating and sensitiz-ing effects of ACh that increase the responseto secretin. However, a direct vagal compon-ent of stimulation is initiated during thecephalic phase. Sham feeding produces apancreatic secretory response that, of course,is blocked totally by vagotomy. In dogs, thecephalic phase accounts for approximately20% of the response to a meal. The stimulifor the cephalic phase of pancreatic secretionare the conditioned reflexes, smell, taste,chewing, and swallowing. Afferent impulsestravel to the vagal nucleus. Vagal efferents tothe pancreas stimulate both the ductule and

the acinar cells to secrete. Stimulation is me-diated by ACh and has a greater effect onthe enzymatic component than it does on theaqueous component. In dogs, a portion ofthe cephalic phase is mediated by gastrin re-leased by the vagus. Gastrin has approxim-ately half the potency of CCK for activatingthe acinar cells. Gastrin plays only a minorrole, if any, in the regulation of human pan-creatic secretion. These mechanisms are il-lustrated in Figure 9-4.

FIGURE 9-4 Mechanisms involved in thestimulation of pancreatic secretion duringthe cephalic phase. Dashed lines represent

minor effects. ACh, acetylcholine;, bicarbonate; H2O, water.

Gastric PhaseThe stimulation of pancreatic secretion ori-ginating from food in the stomach is medi-ated by the same mechanisms that are in-volved in the cephalic phase. Distention ofthe wall of the stomach initiates vagovagalreflexes to the pancreas. Gastrin is releasedby protein digestion products and distention(see Chapter 8), but again it plays little orno role in the stimulation of the human pan-creas.

Intestinal PhaseThe presence of digestion products and H+ inthe human small intestine accounts for 70%to 80% of the stimulation of pancreatic secre-tion. Secretin and CCK account for almost allthe hormonal stimulation of pancreatic se-cretion. The stimulus for the alkaline com-

ponent (water and ) is secretin re-leased from the S cells by gastric acid andhigh concentrations of long-chain fatty acids.Secretion of the enzymatic component fromthe acinar cells is stimulated by CCK re-leased from the I cells by fat and protein di-gestion products. Current evidence indicatesthat human acinar cells lack CCK receptors.Because vagotomy blocks the secretory re-sponse to infusions of physiologic doses ofCCK, in humans, CCK acts by stimulatingvagal afferent receptors and initiating vago-vagal reflexes. This stimulation depends oncholinergic signaling because atropineblocks pancreatic secretion in response to

CCK. In rodents, acinar cells express CCK re-ceptors and are activated directly by the hor-mone.

The only potent releaser of secretin is H+.The duodenal pH threshold for secretin re-lease is 4.5. Secretin release rises almost lin-early as the pH is lowered to 3 ( Fig. 9-5).Lowering the pH below 3 does not lead togreater release of secretin, provided theamount of titratable acid entering the duo-denum is held constant. Below pH 3, secretin

release and pancreatic secretion arerelated only to the amount of titratable acidentering the duodenum per unit of time. Asmore acid enters the gut, more secretin-con-taining cells are stimulated to release hor-mone. Thus at a constant pH, the amount ofsecretin released is a function of the length ofgut acidified. Secretin can be released fromthe entire duodenum and jejunum, and theamount of hormone available for release ap-

pears to be constant per centimeter of prox-imal small intestine.

FIGURE 9-5 Pancreatic bicarbonate (

) output in response to variousduodenal pH values. The output of

is used as an index of secretin re-lease.

During the response to a normal meal,however, only the duodenal bulb and prox-imal duodenum are acidified sufficiently to

release secretin. The pH of the proximal duo-denum rarely drops below 4 to 3.5. This find-ing raises doubts about whether sufficientsecretin is released by a meal to account for

the high rates of pancreatic and wa-ter secretion normally seen. If the pH of thegastric contents entering the duodenum iskept at 5 or higher by automatic titration, thepancreatic response is typical of CCK andACh acting alone (a small volume ofenzyme-rich juice). Dropping the pH evenslightly below the threshold for secretin re-lease leads to large increases in volume and

secretion. The conclusion thereforeis that the effects of a small amount of secret-in are potentiated by CCK and ACh. In hu-mans, this potentiation is the result of AChalone.

This is an important physiologic interac-tion of two gastrointestinal (GI) hormonesand cholinergic reflexes and is demonstrateddirectly by the experiment outlined in Figure

9-6. Phenylalanine, a potent releaser of CCKand initiator of vagovagal reflexes, producesa small increase in volume when givenalone. If, however, the same dose is infusedinto the gut while a low dose of secretin isgiven intravenously, the output of the pan-creatic alkaline component increases tolevels seen during a meal. Vagotomy greatlydecreases the potentiated response.Physiologically, then, in humans, the

volume and responses to a meal res-ult from small amounts of secretin releasedby duodenal acidification, potentiated byACh from vagovagal reflexes activated byCCK.

FIGURE 9-6 Pancreatic bicarbonate (

) output in response to continualperfusion of the duodenum with phenylalan-ine, to continuous intravenous infusion ofsecretin, and to the combination of the twostimuli. The response to secretin is greatlypotentiated by endogenous phenylalanine.

Secretin has been referred to as “nature’santacid” because most of its physiologic andpharmacologic actions decrease the amountof acid in the duodenum. For example, it

stimulates secretion of from thepancreas and liver and inhibits gastric secre-tion and emptying, as well as gastrin release.

CCK is the principal humoral regulator ofenzyme secretion from the pancreatic acinarcells. It is released in response to amino acidsand fatty acids in the small intestine. Only L-isomers of amino acids are effective. In dogs,phenylalanine and tryptophan are potent re-leasers. Alanine, leucine, and valine are lesseffective. Phenylalanine, methionine, andvaline appear to be potent releasers in hu-mans. CCK is distributed evenly over thefirst 90 cm of intestine, and infusion of L-phenylalanine below the ligament of Treitzproduces pancreatic enzyme responsesequal to those seen after infusion near thepylorus. Thus the amount of CCK released

depends on the load and length of bowelexposed, as well as on the concentration ofamino acids present.

Strong evidence indicates that some pep-tides, as well as single amino acids, also re-lease CCK. Three dipeptides, all of whichcontain glycine (glycylphenylalanine, glycyl-tryptophan, and phenylalanylglycine), are ef-fective. Dipeptides or tripeptides of glycine,or glycine itself, are ineffective. Evidence ex-ists that some peptides containing at leastfour amino acids are also effective. Undiges-ted protein does not release CCK. After aprotein meal, therefore, many different spe-cific protein products evoke CCK releaseand pancreatic enzyme secretion.

In addition to protein products, fatty acidslonger than eight carbon atoms release CCKand initiate vagovagal reflexes. Lauric,palmitic, stearic, and oleic acids are equal andstrong releasers of CCK. Fat must be in anabsorbable form before release of the hor-mone occurs. The interactions between lu-

minal nutrients and the receptors triggeringthe release of CCK, and of GI hormones ingeneral, are poorly understood. As a result,most of the intracellular mechanisms result-ing in hormone release are unknown. Part ofthe reason for this paucity of information hasbeen the inability to isolate large numbers ofhormone-containing cells from the mucosaof the GI tract.

Active trypsin in the intestinal lumen in-hibits CCK release, and the ingestion of tryp-sin inhibitors strongly stimulates the releaseof the hormone. Diversion of pancreatic se-cretion from the gut lumen also increasesplasma CCK. These data suggest the exist-ence of a feedback mechanism controllingthe release of CCK. Additional studies in-dicate that dietary protein products bind orinhibit trypsin, which would otherwise in-activate a CCK-releasing peptide. Several ofthese peptides have been identified, but theirphysiologic significance remains to be elu-cidated.

The mechanisms resulting in the stimula-tion of pancreatic secretion during the intest-inal phase are illustrated in Figure 9-7.

FIGURE 9-7 Mechanisms involved in thestimulation of pancreatic secretion duringthe intestinal phase in the human. Dashedlines indicate potentiative interactions. AAs,amino acids; ACh, acetylcholine; CCK,cholecystokinin; FAs, fatty acids; H+, hydro-

gen ion; , bicarbonate; H2O, wa-ter.

Cellular Basis forPotentiationThe concept of potentiation requires that thepotentiating stimuli act on different mem-brane receptors and trigger different cellularmechanisms for the stimulation of secretion.Some of the steps in these mechanisms havebeen elucidated for the rodent pancreaticacinar cell; these are illustrated in Figure 9-8.

FIGURE 9-8 Receptors on the rodent pan-creatic acinar cell. Different second mes-sengers for the stimulants indicate differentcellular mechanisms for stimulation andprovide the basis for potentiation. ACh,acetylcholine; ATP, adenosine triphosphate;Ca2+, calcium; cAMP, cyclic adenosinemonophosphate; CCK, cholecystokinin.

Secretin binding to its receptor triggers anincrease in adenylyl cyclase activity that res-ults in the synthesis of cAMP. ACh and CCKbind to separate receptors, but both increase

intracellular Ca2+. The Ca2+ is mobilizedprimarily from the plasma membranes andRER of the acinar cells. Both CCK and AChalso increase diacylglycerol and inositol tri-phosphate (IP3) production from phos-phatidylinositol. It is likely that one of thesebreakdown products is the intracellular mes-senger for Ca2+ release. Interactions betweensecretin and ACh or secretin and CCK resultin potentiation. However, the effects of com-bining CCK and ACh, which trigger identic-al mechanisms, are only additive. Glucagonand vasoactive intestinal peptide (VIP) alsoincrease cAMP. Gastrin, gastrin-releasingpeptide, and substance P increase Ca2+ inacinar cells. However, no strong evidence in-dicates that these substances play an import-ant role in the physiologic regulation of pan-creatic secretion.

The final steps in the process leading toenzyme secretion have not been elucidated,but they involve the phosphorylation of

structural and regulatory proteins. Potenti-ation occurs because Ca2+ and cAMP lead tothe activation of different kinases and thephosphorylation of different proteins. Theforegoing interactions have been worked outwith guinea pig isolated pancreatic acini. Se-cretin does not potentiate the effects of CCKand ACh in dogs or humans. A system simil-ar to this, however, is a likely explanation ofthe potentiation in all species in which it oc-curs. Thus similar events may be predictedfor the human ductule cell, in which secretin(cAMP) is potentiated by ACh (Ca2+).

Response to a MealAs digestion and mixing of food proceed inthe stomach, buffers present in proteins andpeptides become saturated with H+, and thepH drops to approximately 2. The maximumload of titratable acid (free H+ plus bound H+)delivered to the duodenum is 20 to 30 mEq/hour. This is approximately equal to the max-imal capacity of the stomach to secrete acid,which, in turn, equals the ability of the pan-

creas to secrete when it is maximallystimulated. To raise the pH of the duodenum,the undissociated H+, as well as the free H+,must be neutralized. This is accomplishedrapidly in the first part of the duodenum, andthe pH of the chyme is raised quickly from2 at the pylorus to more than 4 beyond theduodenal bulb. Some neutralization occurs by

absorption of H+ and secretion of bythe gut wall. An additional amount of H+ is

neutralized by in the bile. The con-tributions of the gut mucosa and bile aresmall, however, and the greatest proportionof acid by far is neutralized by the largevolume of pancreatic juice secreted into thelumen.

Within a few minutes after chyme entersthe duodenum, a sharp rise in the secretionof pancreatic enzymes occurs. Within 30minutes, enzyme secretion peaks at levelsapproximately 70% to 80% of those attain-able with maximal stimulation by CCK andcholinergic reflexes. Enzyme secretion con-tinues at this rate until the stomach is empty.The enzyme response to a meal may be keptbelow maximum by the presence of humoralinhibitors of pancreatic secretion. This is theproposed function of pancreatic polypep-tide.

Pancreatic enzyme secretion is able to ad-apt to the diet. In other words, ingestion ofa high-protein, low-carbohydrate diet over

several days increases the proportion of pro-teases and decreases the proportion of amyl-ase in pancreatic juice. This type of responseis now known to be hormonally regulated atthe level of gene expression. CCK increasesthe expression of the genes for proteases anddecreases the expression for amylase. Secret-in and gastric inhibitory peptide (GIP) in-crease the expression of the gene for lipase.The mechanism to increase amylase gene ex-pression under normal conditions is notknown, although insulin regulates amylaselevels in diabetes.

Insulin potentiates the secretory responsesto CCK and secretin, a finding that probablyaccounts for the reduced pancreatic enzymesecretion in human diabetic patients whohave no obvious pancreatic disease. Insulinalso is necessary to maintain normal rates ofpancreatic protein synthesis and stores of di-gestive enzymes.

CLINICALAPPLICATIONSAbnormal pancreatic secretionoccurs with diseases such aschronic and acute pancreatitis,cystic fibrosis, and kwashiorkor,as well as with tumors that in-volve the gland itself. Changes insecretion during the course ofone of these diseases depend onthe stage of development of thedisease. Most patients withchronic pancreatitis have de-creased volume and bicarbonateoutput, whereas those with acutepancreatitis often have normalsecretion. Both volume and en-zyme content of pancreatic juiceare decreased by cystic fibrosis.Tumors of the pancreas fre-quently decrease the volume ofsecretion. In kwashiorkor,

severe protein deficiency, the al-kaline and enzymatic compon-ents are depressed, but amylasesecretion continues after trypsin,chymotrypsin, and lipase activit-ies are no longer found.

Pancreatitis is an inflammat-ory disease of the pancreas thatoccurs when proteases are activ-ated within the acinar cells.These enzymes are synthesizedin inactive forms and normallyare activated only when theyreach the intestine. The mostcommon causes of this conditionare excessive alcohol consump-tion and blockage of the pancre-atic duct. Blockage is usually theresult of gallstones and fre-quently occurs at the ampulla ofVater. Secretions build up be-hind the obstruction, and trypsin

accumulates and activates otherpancreatic proteases, as well asadditional trypsin. Eventually,the normal defense mechanismsare overwhelmed, and pancreat-ic tissue is digested. In additionto synthesizing proteases as in-active proenzymes, the pancreashas several other mechanisms toprevent damage. First, enzymesare membrane bound from thetime of synthesis until they aresecreted from zymogen granules.Second, acinar cells contain atrypsin inhibitor, which destroysactivated enzymes. Third, tryp-sin itself is capable of autodiges-tion. Fourth, some lysosomal en-zymes also degrade activated zy-mogens. Approximately 10% ofpancreatitis cases are hereditary.Mutations associated with the

normal defense mechanismshave been identified as account-ing for most of these cases. Twomutations occur in the trypsingene itself. One (R122H) en-hances trypsin activity by im-pairing its autodigestion. Theother (N29I) leads to an in-creased rate of autoactivation. Inaddition, mutations in the nativetrypsin inhibitor have beenshown to increase the risk of dis-ease.

Cystic fibrosis is characterizedby decreased chloride (Cl−) secre-tion of many epithelial tissuesand the inability of cyclic aden-osine monophosphate (cAMP) toregulate Cl− conductance. Asmentioned earlier, good eviden-ce indicates that the ion channelfor Cl− in the apical membrane of

the duct cell is the cystic fibrosistransmembrane conductanceregulator that is regulated bycAMP. Failure to synthesize thisprotein in its normal state or fail-ure to insert it properly in the ap-ical membrane results in cysticfibrosis and a severe decrease ofductal secretion. As a result, pro-teinaceous acinar secretions be-come concentrated and precipit-ate within the duct lumen, thusblocking small ducts and eventu-ally destroying the gland.

Pancreatic enzyme secretionmust be reduced by more than80% to produce steatorrhea. If apatient has steatorrhea, it is ne-cessary only to measure the con-centration of any pancreatic en-zyme in the jejunal content after

a meal to determine whether thecondition is pancreatic in origin.

Pancreatic exocrine function isassessed by measuring basal se-cretion and secretion stimulatedby secretin and/or cholecys-tokinin (CCK). These functiontests are performed on a fastingpatient. A double-lumen naso-gastric tube is used. One tubeopens into the stomach to draingastric contents that would oth-erwise empty into the duo-denum; the other collects duo-denal juice that is assumed to belargely pancreatic in origin. In-terpretation of the test is imped-ed by contaminating biliary se-cretions. Changes in secretiondepend on the stage of develop-ment of various diseases andmay vary from patient to patient.

For these reasons, pancreaticfunction tests are not reliable inthe diagnosis of individual dis-eases but are used to assess over-all pancreatic function.

Summary1. Pancreatic secretion consists of an aqueous

component from the duct cells andan enzymatic component from the acinarcells.

2. The duct cells actively secrete intothe lumen, and Na+ and water follow downelectrical and osmotic gradients, respectively.3. The composition of pancreatic juice varieswith the rate of secretion. At low rates, Na+

and Cl– predominate; at high rates, Na+ and

predominate.4. Pancreatic enzymes are essential for the di-gestion of all major foodstuffs and are storedin zymogen granules of acinar cells before se-cretion.5. The primary stimulant of the aqueous com-ponent is secretin, whose effects are potenti-ated by CCK and ACh.

6. During the cephalic phase of secretion,vagal stimulation results in a low volume ofsecretion containing a high concentration ofenzymes. This secretion is produced by theacinar cells.7. During the intestinal phase, acid (pH lessthan 4.5) releases secretin. Fats and aminoacids release CCK, which activates vagal af-ferents. The resulting vagovagal reflexes me-diated by ACh stimulate enzyme secretionfrom the acinar cells. Stimulants using differ-ent second messengers potentiate each other.

KEY WORDS ANDCONCEPTSAqueous componentEnzymatic/protein componentAcinar cellsDuctule cellsCentroacinar cellsIslets of LangerhansPotentiationChronic pancreatitis

Tumors of the pancreasKwashiorkorCystic fibrosisSteatorrhea

Suggested ReadingsAnagostides, A., Chadwick, V. S., Selden, A. C., et al.

Sham feeding and pancreatic secretion: evidencefor direct vagal stimulation of enzyme output.Gastroenterology. 1984; 87:109–114.

Argent, B. E., Gray, M. A., Steward, M. C., Case, R.M., Cell physiology of pancreatic ductsJohnson,L. R., eds. Physiology of the GastrointestinalTract, ed 5, vol 2. San Diego: Elsevier, 2012.

Gorelick, F. S., Jamieson, J. D., Structure-function re-lationships in the pancreatic acinar cellJohnson, L.R., eds. Physiology of the Gastrointestinal Tract,ed 5, vol 2. San Diego: Elsevier, 2012.

Jensen, R. T., Receptors on pancreatic acinar cell-sJohnson, L. R., eds. ed 3. Physiology of the

Gastrointestinal Tract. Raven Press, New York,1994.

Ji, B., Bi, Y., Simeone, D., et al. Human pancreaticacinar cells lack functional responses to cholecys-tokinin and gastrin. Gastroenterology. 2001;121:1380–1390.

Logsdon, C. D., Pancreatic enzyme secretion(physiology)Johnson, L. R., eds. Encyclopedia ofGastroenterology; vol 3. Academic Press, SanDiego, 2004:68–75.

Meyer, J. H., Way, L. W., Grossman, M. I. Pancreaticresponse to acidification of various lengths ofproximal intestine in the dog. Am J Physiol. 1970;219:971–977.

Liddle, R. A., Regulation of pancreatic secretionJohn-son, L. R., eds. Physiology of the GastrointestinalTract, ed 5, vol 2. San Diego: Elsevier, 2012.

Solomon, T. E., Grossman, M. I. Effect of atropineand vagotomy on response of transplanted pan-creas. Am J Physiol. 1979; 236:E186–E190.

Williams, J. A., Yule, D. I., Stimulus-secretion coup-ling in the pancreatic acinar cellsJohnson, L. R.,eds. Physiology of the Gastrointestinal Tract, ed 5,vol 2. San Diego: Elsevier, 2012.

1 0

Bile Secretion andGallbladder Function

Object ives

Describe the constituents of bile and theirfunctions.Understand the solubility of the bile acidsand bile salts and how it affects their reab-sorption in the small bowel.Describe the enterohepatic circulation andits role in bile acid synthesis and the secre-tion of bile.

Understand the process involved in theexcretion of bile pigments and its relation-ship with jaundice.Explain the function of the gallbladder.Describe the regulation of bile secretionfrom the liver and its expulsion from thegallbladder.Explain the abnormalities that may lead tothe formation of gallstones.

Bile is responsible for the principal digestivefunctions of the liver. Bile in the small intest-ine is necessary for the digestion and absorp-tion of lipids. The problem of the insolubil-ity of fats in water is solved by the constitu-ents of bile. The bile salts and other organ-ic components of bile are responsible in partfor emulsifying fat so that it can be digestedby pancreatic lipase. The bile acids also takepart in solubilizing the digestion products

into micelles. Micellar formation is essentialfor the optimal absorption of fat digestionproducts. Bile also serves as the vehicle forthe elimination of a variety of substancesfrom the body. These include endogenousproducts such as cholesterol and bile pig-ments, as well as some drugs and heavymetals.

Overview of the BiliarySystemFigure 10-1 is a schematic illustration of thebiliary system and the circulation of bile acidsbetween the intestine and liver. Bile is con-tinuously produced by the hepatocytes. Theprincipal organic constituents of bile are thebile acids, which are synthesized by the hep-atocytes. The secretion of bile acids carrieswater and electrolytes into the bile by osmoticfiltration. Additional water and electrolytes,primarily sodium bicarbonate (NaHCO3), areadded by cells lining the ducts. This lattercomponent is stimulated by secretin and is es-sentially identical to the aqueous componentof pancreatic secretion. The secretion of bileincreases pressure in the hepatic ducts andcauses the gallbladder to fill. Within the gall-bladder, bile is stored and concentrated by theabsorption of water and electrolytes. When a

meal is eaten, the gallbladder is stimulatedto contract by CCK and vagal stimulation.Within the lumen of the intestine bile parti-cipates in the emulsification, hydrolysis, andabsorption of lipids. Most bile acids are ab-sorbed either passively throughout the in-testine or actively in the ileum. Bile acids lostin the feces are replaced by synthesis in thehepatocytes. The absorbed bile acids are re-turned to the liver via the portal circulation,where they are extracted actively from theblood. Together with newly synthesized bileacids, the returning bile acids are secretedinto the bile canaliculi. Canalicular bile issecreted by ductule cells in response to theosmotic effects of anion transport. In hu-mans, almost all bile formation is driven bybile acids and is therefore referred to as bileacid dependent. The portion of bile stim-ulated by secretin and contributed by theducts is termed bile acid independent orductular secretion.

FIGURE 10-1 Overview of the biliary sys-tem and the enterohepatic circulation of bileacids. Solid arrows indicate active transportprocesses. ACh, acetylcholine; Ca2+, calci-um; CCK, cholecystokinin; Cl−, chloride; H+,

hydrogen ion; , bicarbonate; H2O,water; K+, potassium; Na+, sodium. (From

Johnson LR: Essential Medical Physiology, 3rd ed. Philad-

elphia, Academic Press, 2003, p 521.)

Constituents of BileBile is a complex mixture of organic and in-organic components. Taken separately, someof the components are insoluble and wouldprecipitate out of an aqueous medium.Normally, however, bile is a homogeneousand stable solution whose stability dependson the physical behavior and interactions ofits various components.

Bile acids, the major organic constituentsof bile, account for approximately 50% of thesolid components. Chemically, they arecarboxylic acids with a cyclopentanoperhy-drophenanthrene nucleus and a branchedside chain of three to nine carbon atoms thatends in a carboxyl group ( Fig. 10-2). They arerelated structurally to cholesterol, from whichthey are synthesized by the liver. Indeed, thesynthesis of bile acids is a major pathway forthe elimination of cholesterol from the body.

Conversion of cholesterol to bile acids occursvia two main synthetic pathways.

FIGURE 10-2 Principal organic constitu-ents of bile. The two primary bile acids maybe converted to secondary bile acids in theintestine. Each of the four bile acids may beconjugated to either glycine or taurine toform bile salts. The R-groups of lecithin rep-resent fatty acids. pKa, negative log of dis-sociation constant. (From Johnson LR: Essential

Medical Physiology, 3rd ed. Philadelphia, Academic Press,

2003, p 522.)

The major pathway begins with the rate-limiting step of 7α-hydroxylation of choles-terol by the hepatic enzyme 7α-hydroxylase.A secondary pathway begins with the con-version of cholesterol to27-hydroxycholesterol, a reaction that takesplace in many tissues. Four bile acids arepresent in bile, along with trace amounts ofothers that are modifications of the four. Theliver synthesizes two bile acids, cholic acidand chenodeoxycholic acid. These are theprimary bile acids (see Fig. 10-2). Within thelumen of the gut, a fraction of each acid is de-hydroxylated by bacteria to form deoxychol-ic acid and lithocholic acid. These are calledsecondary bile acids. All four are returned tothe liver in the portal blood and are secretedinto the bile. Their relative amounts in bileare approximately four cholic to two chen-

odeoxycholic acid to one deoxycholic to onlysmall amounts of lithocholic acid.

The solubility of bile acids depends on thenumber of hydroxyl groups present and thestate of the terminal carboxyl group. Cholicacid, with three hydroxyl groups, is the mostsoluble, whereas lithocholic, a monohydroxyacid, is least soluble. The dissociation con-stant (pK) of the bile acids is near the pHof the duodenal contents, so there are rel-atively equal amounts of protonated (insol-uble) forms and ionic (soluble) forms. Theliver, however, conjugates the bile acids tothe amino acids glycine or taurine with apKa of 3.7 and 1.5, respectively. Thus at thepH of duodenal contents, bile acids arelargely ionized and water soluble. Conjug-ated bile acids exist as salts of variouscations, primarily Na+, and are referred to asbile salts (see Fig. 10-2).

Several features are unique to the bileacids and account for their behavior in solu-tion. Three-dimensionally, the hydroxyl and

carboxyl groups are located on one side ofthe molecule. The bulk of the molecule iscomposed of the nucleus and several methylgroups ( Fig. 10-3). This structure rendersbile acids amphipathic to the extent that thehydroxyl groups, the peptide bond of theside chain, and either the carbonyl or sulf-onyl group of glycine or taurine are hydro-philic, and the cholesterol nucleus andmethyl groupings are hydrophobic. In solu-tion, the behavior of bile acids depends ontheir concentration. At low concentrations,little interaction occurs among bile acid mo-lecules. As the concentration is increased, apoint is reached at which aggregation of themolecules takes place. These aggregates arecalled micelles, and the point of formationis called the critical micellar concentration.Hydrophobic regions of the micelles interactwith one another, and the hydrophilic re-gions interact with the water molecules (seeFig. 10-3).

FIGURE 10-3 Structures of components ofmicelles and micelles themselves. A, Rep-resentations of bile salt, lecithin, and choles-terol molecules illustrating the separation ofpolar and nonpolar surfaces. B, Cross sec-tion of a micelle showing the arrangement ofthese molecules and the principal productsof fat digestion. Micelles are cylindrical diskswhose outer curved surfaces are composed

of bile salts. OH, hydroxyl. (From Johnson LR: Es-

sential Medical Physiology, 3rd ed. Philadelphia, Academic

Press, 2003, p 523.)

The second most abundant group of or-ganic compounds in bile consists of thephospholipids, and the major ones are thelecithins (see Fig. 10-3). Phospholipids alsoare amphipathic, insofar as the phos-phatidylcholine grouping is hydrophilic,whereas the fatty acid chains are hydro-phobic. Although amphipathic, the phos-pholipids are not soluble in water but formliquid crystals that swell in solution. In thepresence of bile salts, however, the liquidcrystals are broken up and solubilized as acomponent of the micelles. Bile salts possessa large capacity to solubilize phospholipids;2 moles (mol) of lecithin are solubilized by1 mol of bile salts. The combination of bilesalts and phospholipids also is better ableto solubilize other lipids—mainly cholesterol

and the products of fat digestion—than is asimple solution of bile salts.

A third organic component, cholesterol,is present in small amounts and contributesapproximately 4% to the total solids of bile.Although present in small amounts, bile cho-lesterol is important because it may be ex-creted and therefore helps regulate bodystores of cholesterol. Cholesterol appearsmainly in the nonesterified form and is in-soluble in water. In the presence of bile saltsand phospholipids, however, it is solubilizedas part of the micelle. Because it is a weaklypolar substance, cholesterol is found in theinterior of the micelle, where the hydro-phobic portions of the bile salts, phospholip-ids, monoglycerides, and fatty acids interact(see Fig. 10-3). Within the liver, ducts, andgallbladder, bile is normally present as a mi-cellar solution.

The fourth major group of organic com-pounds found in bile comprises the bile pig-ments. These constitute only 2% of the total

solids, and bilirubin is the most important.Chemically, bile pigments are tetrapyrrolesand are related to the porphyrins, fromwhich they are derived. In their free form,bile pigments are insoluble in water.Normally, however, they are conjugatedwith glucuronic acid and are rendered sol-uble. Unlike the other organic compoundsjust mentioned, bile pigments do not takepart in micellar formation. As their name im-plies, they are highly colored substances.Other than being responsible for the normalcolor of bile and feces, the pigment proper-ties of these compounds are used to assessthe level of function of the liver.

In addition to the organic compounds justdiscussed, many inorganic ions are foundin bile. The predominant cation is Na+, ac-companied by smaller amounts of potassium(K+) and calcium (Ca2+). The predominant in-organic anions are chloride (Cl−) and

. Normally, the total number of in-

organic cations exceeds the total number ofinorganic anions. No anion deficit occurs,however, because the bile acids, which pos-sess a net negative charge at the pH valuesfound in bile, account for the difference. Bileis isosmotic even though the number ofcations present is larger than expected. Be-cause they are highly charged molecules, thebile acids attract a layer of cations that serveas counterions. These counterions are tightlyassociated with the micelles and thus exertlittle osmotic activity.

Bile SecretionFunctional Histology Of TheLiverThe functional organization of the liver isshown schematically in Figure 10-4. The liveris divided into lobules organized around acentral vein that receives blood through sep-arations surrounded by plates of hepatocytes.The separations are called sinusoids, and theyin turn are supplied by blood from both theportal vein and the hepatic artery. The platesof hepatocytes are no more than two cellsthick, so every hepatocyte is exposed toblood. Openings between the plates ensurethat the blood is exposed to a large surfacearea. The hepatocytes remove substancesfrom the blood and secrete them into the bili-ary canaliculi lying between the adjacent hep-atocytes. The bile flows toward the periphery,countercurrent to the flow of the blood, and

drains into bile ducts. This countercurrentrelationship minimizes the concentrationdifferences between substances in the bloodand in the bile and contributes to the liver’sefficiency in extracting substances from theblood.

FIGURE 10-4 Schematic diagram of therelationship between blood vessels, hepato-cytes, and bile canaliculi in the liver. Eachhepatocyte is exposed to blood at onemembrane surface and a bile canaliculus atthe other. (From Johnson LR: Essential Medical

Physiology, 3rd ed. Philadelphia, Academic Press, 2003, p

524.)

Bile Acids And TheEnterohepatic CirculationThe secretion of bile depends heavily on thesecretion of bile acids by the liver. Oncesecreted, bile acids undergo an interestingjourney (see Fig. 10-1). First, they may bestored in the gallbladder. Then they are pro-pelled into and through the small intestine,where they take part in the digestion andabsorption of lipids. Most of the bile acidsthemselves are absorbed from the intestineand travel via the portal blood to the liver,where they are taken up by the hepatocytesand resecreted. This process is termed theenterohepatic circulation.

Bile acids are secreted continuously by theliver. The rate of secretion, however, varieswidely. Early experiments demonstratedthat the rate of secretion depended on theamount of bile acids delivered to the liver viathe blood; the more acids in the portal blood,the greater the secretion of bile. The amount

of bile acids in the portal blood depends onthe amount absorbed from the small intest-ine. The amount of bile acids in the intestine,in turn, depends on the digestive state ofthe individual. Between meals, most bilesecreted by the liver is stored in the gallblad-der, with only small amounts delivered in-termittently to the small intestine. During ameal, the gallbladder empties its contents in-to the duodenum in a more continuous pat-tern. The ejected bile acids are then resorbedfrom the intestine and are secreted again bythe liver.

Although many different bile acids arefound in the bile, only cholic acid and chen-odeoxycholic acid appear to be synthesizedfrom cholesterol in significant amounts byhuman hepatocytes. For this reason, they arecalled “primary” bile acids. Their synthesisby the liver is a continuous but regulatedprocess. The amount synthesized dependson the amount of bile acids returned to theliver in the enterohepatic circulation. When

most of the bile acids secreted by the liverare returned, synthesis is low, but when thesecreted acids are lost from the enterohepaticcirculation, the rate of synthesis is high. Bileacids extracted from the portal blood act tofeedback inhibit 7α-hydroxylase, the rate-limiting enzyme for the synthesis of bileacids from cholesterol. Normally, there are2.5 g of bile salts in the enterohepatic circula-tion. If the absorptive processes in the intest-ine and liver are functioning properly, onlyapproximately 0.5 g is lost daily. Synthes-is is regulated to replenish this loss. If theenterohepatic circulation is interrupted (e.g.,by a fistula draining bile to the outside), therate of synthesis becomes maximal. In hu-mans, this amounts to 3 to 5 g per day. Inpatients incapable of reabsorbing bile acids,the maximal rate of synthesis equals the totalamount of bile acids secreted by the liver.Deoxycholic acid, lithocholic acid, and other“secondary” bile acids are produced in theintestine through the action of microorgan-

isms on primary bile acids. These acids thenare absorbed along with the primary bileacids, taken up by the hepatocytes, conjug-ated with taurine and glycine, and secretedin the bile. The bile acid pool may circulatethrough the enterohepatic circulation severaltimes during the digestion of a meal, so that15 to 30 g bile acids may enter the duodenumduring a 24-hour period.

The enterohepatic circulation of bile acidsis carried out by both active and passivetransport processes ( Fig. 10-5). The more hy-drophobic bile acids, which are those withfewer hydroxyl groups and those that havebeen deconjugated, are absorbed passivelythroughout the intestine. The more hydro-philic acids and the remaining hydrophobicacids are absorbed by an active process inthe ileum. Uptake across the apical mem-brane of the enterocytes is mediated by aspecific Na+-dependent transport protein.Cytoplasmic binding proteins transport theacids through the cell to the basolateral

membrane. Transport across the basolateralmembrane out of the cell is mediated by anNa+-independent anion exchange processthat involves a carrier different from the oneon the apical membrane. As stated previ-ously, the ileal transport process is highly ef-ficient, delivering more than 90% of the bileacids to the portal blood.

FIGURE 10-5 Enterohepatic circulation ofbile acids. Bile acids are actively secretedby the liver. Once in the intestine they parti-cipate in the digestion and absorption of lip-ids. As they are propelled toward the distalsmall bowel, some of the “primary” acids arealtered and become “secondary” acids. Themore hydrophobic bile acids are absorbedpassively throughout the intestine. Themore hydrophilic acids are absorbed by asodium-coupled active transport processthat is localized to the ileum. A minor frac-

tion of bile acids is not absorbed but is in-stead propelled into the colon. The ab-sorbed bile acids are transported via theportal circulation to the liver, where they areextracted actively from the blood (at a rateof almost 100%) and resecreted. Synthesisof new primary acids from cholesterol oc-curs at a rate to compensate for the acidslost from the bowel. Solid arrows denoteactive absorption, secretion, and synthesis;open arrows denote passive absorption andpropulsion of contents by contractions of theintestine.

In the liver, additional transport processesremove bile acids from the portal blood. Up-take across the basolateral or sinusoidalmembrane of the enterocytes is mediatedprimarily by two types of systems. Onegroup includes a specific Na+-coupled trans-porter protein, the Na+ taurocholate cotrans-porting polypeptide (NTCP), which cantransfer both conjugated and unconjugatedbile acids. A group of Na+-independent

transporters includes the organic aniontransport proteins (OATPs), which can takeup both bile acids and other organic anions.At the canaliculus, bile acids and other or-ganic anions appear to be secreted by at leasttwo adenosine triphosphate (ATP)-depend-ent processes. One of these is termed the bilesalt excretory pump (bsep), and the other isthe multidrug resistance protein 2 (mrp2). Thehepatic transport of bile acids also is highlyefficient. Practically all bile acids containedin the portal blood are removed during onepassage through the liver. The process doeshave a transport maximum, but this is sel-dom reached.

Cholesterol And PhospholipidsCholesterol and phospholipids, primarily le-cithins, also are secreted by the hepatocytes.The exact mechanisms of secretion are notknown, but secretion appears to depend, inpart, on the secretion of bile acids. The high-

er the rate of bile acid secretion is, the higherthe rate of cholesterol and phospholipid se-cretion will be. Once secreted into the intest-ine along with the other components of bile,cholesterol and lecithin are mixed with andhandled as ingested cholesterol and lecithin(see Chapter 11).

BilirubinThe primary bile pigment in humans, biliru-bin, is derived largely from the metabolicbreakdown of hemoglobin ( Fig. 10-6). Mostof the hemoglobin comes from aged redblood cells (RBCs) that are disposed of bycells of the reticuloendothelial (RE) system.In the RE cells, hemoglobin is split intohemin and globin. The hemin ring is openedand oxidized, and the iron is removed toform bilirubin, which is then transported viathe blood from the cells of the RE system tothe hepatocytes. In transit, bilirubin is tightlybound to plasma albumin; very little is free

in the plasma. Hepatocytes can extract bi-lirubin from blood, conjugate it withglucuronic acid, and secrete the conjugatedproduct into the bile. Bilirubin secretion intothe bile by the hepatocytes is mediated by anactive anion transport system. This systemis different from the one for active transportof bile acids, but it is shared by certain oth-er organic anions (e.g., sulfobromophthalein[Bromsulphalein, or BSP], various radi-opaque dyes). Some evidence indicates thatone of the OATPs participates in the trans-port of bilirubin.

FIGURE 10-6 Excretion of bile pigments.Bilirubin is produced by cells of the reticu-loendothelial (RE) system from aged redblood cells (RBCs). The unconjugated pig-ment is then carried, tightly bound to plasmaalbumin, to the liver. There it is activelytaken up, conjugated with glucuronic acid,and secreted into the bile. The water-sol-uble conjugates are propelled along the in-testine. In the distal small bowel and colon a

portion of the conjugated pigment is actedon by bacteria and becomes unconjugatedbilirubin and other pigments. Some of thesepigments are absorbed passively into theblood and either returned to the liver andresecreted or passed through the liver andexcreted by the kidneys. Most, however,pass through the colon and are excreted.Bold arrows indicate active absorption. H2,hydrogen.

Bilirubin is not absorbed from the intestinein any appreciable amount. Some of theproduct, however, is altered in the bowel.Bacteria, primarily in the distal small boweland colon, reduce bilirubin to urobilinogen,which is unconjugated. Some urobilinogenis converted to stercobilin and is excreted inthe feces. Urobilinogen also is absorbed in-to the portal blood and returned to the liv-er. There most is extracted, conjugated, andsecreted into the bile; however, some passesinto the systemic circulation and is excretedby the kidneys. The urobilinogen is oxidized

in the urine to form urobilin. Stercobilin andurobilin are pigments that are in large partresponsible for the color of the feces and ur-ine, respectively. Following damage to theliver, sufficient bilirubin may not be extrac-ted, and the skin takes on a yellow tinge.This condition, termed jaundice, is usuallyespecially noticeable in the eyes. Bilirubin isalso responsible for the yellow color thatbruises develop after several days.

Water And ElectrolytesTwo components of bile water and electro-lyte secretion have been identified. One iscalled bile acid–dependent secretion. Bileacids, regardless of whether they are newlysynthesized or extracted from the portalblood, are the major component activelysecreted by the hepatocytes. Because theyare anions, their secretion is accompanied bythe passive movement of cations into thecanaliculus, which in turn sets up an osmotic

gradient down which water moves ( Fig.10-7). Canalicular bile is thus primarily anultrafiltrate of plasma as far as the concen-trations of water are concerned. In some spe-cies, although not proven in humans, thereis evidence for the active transport of Na+ bythe hepatocytes. The higher the rate of returnof bile acids is to the liver, the faster theyare secreted and the greater is the volume ofbile.

FIGURE 10-7 Secretion and absorption ofwater and electrolytes. The osmotic gradientcreated by the active secretion of bile acids,and perhaps sodium (Na+), causes water tomove from the hepatocytes into the bilecanaliculi. Ions accompany water move-ment, presumably via the process of bulk

flow. Epithelial cells of the bile ducts arecapable of actively absorbing Na+ and chlor-ide (Cl−) and of actively secreting Na+ and

bicarbonate ( ). In the gallbladder,salt absorption is accompanied by the ab-sorption of water, thus concentrating thebile.

The contribution of the bile ducts and duc-tules to bile production is identical to thatof the pancreatic ducts to pancreatic juice.

Secretin stimulates the secretion ofand water from the ductile cells, thereby res-ulting in a significant increase in bile

volume, concentration, and pH anda decrease in the concentration of bile salts.

The mechanism of secretion by theducts of the liver involves active transportand is similar to the mechanism employedby the pancreas. When stimulated by secret-

in, the concentration of the bile may

increase two- or threefold over that ofplasma. This fraction of secretion is calledthe bile acid–independent or the secretin-dependent portion.

Gallbladder FunctionFillingThe primary force responsible for the flowof bile from the canaliculi toward the smallintestine is the secretory pressure generatedby the hepatocytes and ductule epithelium.The hepatic end of the biliary tract is blind,formed by the secretory cells of the liver. Thusas bile is secreted by these cells, pressure inthe ducts rises. The active secretion of bileacids and electrolytes can make biliary secret-ory pressures reach a level of 10 to 20 milli-meters of mercury (mm Hg).

Whether bile flows into the duodenum orinto the gallbladder depends on a balancebetween resistance to the filling of the gall-bladder and resistance to bile flowingthrough the terminal bile duct and sphincterof Oddi. The gallbladder is a distensible mus-cular organ that forms a blind outpouching of

the biliary tract. Its inner surface is linedwith a thin layer of epithelial cells havinghigh absorptive capacity. The sphincter ofOddi is a thickening of the circular muscle ofthe bile duct located at the ductal entranceinto the duodenum. Although this muscleis embedded in the wall of the duodenum,it appears to be an entity separate from theduodenal musculature. Most of the time dur-ing fasting, the gallbladder is readily distens-ible, and the sphincter of Oddi maintainsclosure of the terminal bile duct. Thus bilesecreted by the liver flows into the gallblad-der ( Fig. 10-8).

FIGURE 10-8 A, Bile flow between peri-ods of digestion. Bile is secreted continu-ously by the liver and flows toward the duo-denum. In the interdigestive period the gall-bladder is readily distensible, and thesphincter of Oddi is contracted. Therefore,bile flows into the gallbladder rather than theduodenum. B, On eating, both hormonal(e.g., cholecystokinin [CCK]) and neural

stimuli cause contraction of the gallbladderand relaxation of the sphincter of Oddi.Thus, bile flows into the bowel. Bile secre-tion from the liver increases as bile acidsare returned via the enterohepatic circula-tion.

Concentration Of The BileThe human gallbladder is not a large organand, when full, can accommodate only 20to 50 mL of fluid. During fasting, however,many times that volume of fluid may besecreted by the liver. The discrepancybetween the amount of bile secreted by theliver and the amount stored in the gallblad-der is accounted for by the gallbladder’s abil-ity to concentrate bile. The concentration ofbile salts, bile pigments, and other largewater-soluble molecules may increase by afactor of 5 to 20 as a result of water and elec-trolyte absorption.

Absorption of water and electrolytes ispartly an active process. Na+ absorption canoccur against an electrochemical gradient, isa saturable process, depends on metabolicactivity, and demonstrates other character-istics of an active transport mechanism. Un-like the transport mechanisms for Na+ thatexist in other epithelia, however, transportin the gallbladder is not associated with thegeneration of any measurable electrical po-tential difference. In addition, it is highly de-pendent on the presence of either Cl− or

. Thus it appears as though Na+

transport is coupled with the transport of ananion and is electrically neutral.

As in other epithelial tissues, water move-ment in the gallbladder depends on the act-ive absorption of NaCl and NaHCO3 andthus is entirely passive. The rows of epitheli-al cells of the mucosa have large lateral inter-cellular spaces near the basal membrane andpossess tight junctions at cell apices. Solute

is transported actively from the cells into theintercellular space at the apical ends. Thismovement is then followed by the passivediffusion of water. The movement of watermolecules, however, is such that an osmoticgradient is set up in the intercellular spaces.The solution is hypertonic at the apical endand isotonic at the basal end. In the steadystate, this standing osmotic gradient is main-tained and accounts for the absorption of asolution with fixed osmolality.

Absorption of Na+, Cl−, , and wa-ter influences the concentrations of othersolutes in the bile. Ions such as K+ and Ca2+

become more concentrated. The concentra-tion of bile salts also increases during the ab-sorption of water and electrolytes, often tothe point of the critical micellar concentra-tion. The presence of micelles, which haveminimal osmotic activity, permits the highconcentration of electrolytes, bile salts, phos-

pholipids, and cholesterol to be isotonic ingallbladder bile ( Table 10-1).

TABLE 10-1Approximate Values for Major Compon-ents of Liver and Gallbladder Bile

Reprinted with permission from Johnson LR: Essen-tial Medical Physiology, 3rd ed. Philadelphia, Aca-demic Press, 2003.

Expulsion of BileMost bile secretion occurs during the diges-tion of meals. However, significant amountsare secreted periodically during fasting insynchrony with the migrating motor complex(MMC). The gallbladder contracts, expellingbile, shortly before and during the period ofintense sequential duodenal contractions.Thus bile, along with other secretions, isswept aborally along the bowel by these con-tractions. The exact stimuli and pathways re-sponsible for coordinating gallbladder con-traction with cyclic intestinal motility are notknown, but they appear to involve choliner-gic nerves.

Shortly after eating, the gallbladder mus-culature contracts rhythmically and emptiesgradually (see Fig. 10-8, B). The stimulus forits contraction appears to be primarily hor-monal. Products of food digestion, particu-larly lipids, release cholecystokinin (CCK)

from the mucosa of the duodenum. This hor-mone is carried in the blood to the gallblad-der, where it stimulates the musculature tocontract. CCK is a stimulant of gallbladdermuscle and may act in part by binding toreceptors located directly on smooth musclecells. In vivo, however, much of the actionof CCK appears to be mediated through ex-trinsic vagal and intrinsic cholinergic nerves.The role of other gastrointestinal hormonesis less clear. Gastrin stimulates gallbladdercontraction, but in doses that are well abovethe physiologic range. Secretin appears tohave little direct effect on the gallbladder, al-though it may antagonize (or prevent) theeffects of CCK. Pancreatic polypeptide andsomatostatin both have been shown to de-crease gallbladder contractility and may af-fect gallbladder function in certain diseasestates.

The flow of bile from the gallbladderthrough the common bile duct and into theduodenum is influenced by muscular activ-

ity of the common bile duct, sphincter ofOddi, and duodenum. The bile duct containssmooth muscle cells, and measurements ofits contractile activity have been made in cer-tain species. Some investigators maintainthat peristaltic contractions of the duct dooccur, and that these facilitate movement ofbile into the duodenum. The relative import-ance of this mechanism is not known.

The sphincter of Oddi is a muscular ringsurrounding the opening of the bile duct inthe wall of the duodenum. Its relative contri-butions to the regulation of bile flow some-times are difficult to assess because its ownactivity is influenced by the musculature ofthe duodenum. The sphincter can maintainclosure of the bile duct independently ofactivity of the duodenal musculature. Whenthe duodenum is relaxed, pressures of 12 to30 mm Hg are needed to force fluid througha closed sphincter. However, bile flowthrough an open sphincter of Oddi is influ-enced markedly by the contractile activity of

the duodenum. Bile enters an actively con-tracting bowel in spurts during periods ofduodenal relaxation and stops during peri-ods of contraction. The sphincter, like themuscle of the gallbladder, is controlled bythe hormone CCK. In contrast to its action onthe gallbladder, CCK relaxes the sphincterof Oddi and thereby allows bile to enter theduodenum. In a manner similar to its mech-anism of action on the gallbladder, CCK ap-pears to influence sphincter of Oddi functionby acting on nerves, rather than directly onsmooth muscle.

The role of the autonomic nervous systemin the control of bile flow is not clear. Stim-ulation of parasympathetic nerves causes anincrease in bile flow and contraction of thegallbladder. Stimulation of sympatheticnerves has the opposite effect. Bile flow be-gins shortly after eating and may be part ofthe cephalic phase of digestion. The emo-tional state of the person also has beenshown to influence bile flow.

CLINICALAPPLICATIONSAbnormalities of bile secretioncan result from functionalchanges in the liver, bile ducts,gallbladder, and intestine. Be-cause many of the components ofbile are synthesized and/or act-ively secreted by hepatocytes,metabolic abnormalities of thesecells can result in decreased bileproduction and increasedplasma levels of those constitu-ents normally excreted in the bile(e.g., bile acids, bile pigments).Metabolic abnormalities morecommonly result from the de-struction of hepatocytes by infec-tious agents (e.g., viral hepatitis)and various toxins. However,several conditions are character-ized by genetic deficiencies in

one or more of the steps of bi-lirubin secretion. These deficien-cies also can result in jaundice(a visually detectable buildup ofbile pigments in the blood).

Approximately 10% of thewhite population more than 29years of age in the United Statesis estimated to have gallstones.There are basically two types ofgallstones, cholesterol stones andpigment stones, although bothtypes have a mixed composition.

In many individuals, thequantity of bile produced by theliver may be normal, but thequality may be abnormal. To bestable, bile must contain certainproportions of bile salts, phos-pholipids, and cholesterol. If thepatient has a relative excess ofcholesterol, it may precipitate to

form gallstones. Cholesterolstones are 50% to 75% cholester-ol, and most contain a pigmentcenter (bilirubin) that probablyacted as a nidus for stone form-ation. Approximately 50% of thebile produced by individualswho do not have gallstones is su-persaturated with cholesterol.All bile produced by patientswith cholesterol stones is super-saturated with cholesterol. Innonobese patients with choles-terol stones, the amount of lipidsin bile is decreased. In obese pa-tients, the amount of cholesterolis increased. In both groups, thebile acid pool is reduced forsome reason to about 50% of nor-mal. Supersaturation results incrystal formation and the growthof crystals into stones.

Pigment stones are producedwhen unconjugated bilirubinprecipitates with calcium to forma stone. In normal bile, bilirubinis solubilized by conjugation toglucuronic acid, and approxim-ately only 1% remains unconjug-ated. Gallbladder bile from pa-tients with pigment stones,however, is saturated with un-conjugated bilirubin. The en-zyme β-glucuronidase is re-sponsible for the deconjugationof bilirubin within the gallblad-der. The enzyme is released fromthe wall of the damaged gall-bladder and is present in highconcentrations in a variety ofbacteria, including Escherichiacoli, which may infect the gall-bladder. These unconjugatedpigments, which are less soluble,

then precipitate to form pigmentstones or a nidus for precipita-tion of cholesterol.

Abnormalities of the bile ductsand gallbladder usually are sec-ondary to the processes of ob-struction (e.g., stones, tumor)and infection. Obstruction canresult in severe pain and can leadto reflux of bile into the liver par-enchyma and eventually the sys-temic circulation. Abnormalitiesof intestinal function can alterthe secretion of products that un-dergo enterohepatic circulation.For example, if the terminalileum is diseased or removed,bile salt absorption is reduced.This decreases the bile salt pool(and hence bile salt secretion)and increases synthesis of bileacids by the liver. In addition,

bile acids that enter the colon in-duce water secretion by thecolonic mucosa and causediarrhea.

CLINICAL TESTSThe major tests of bile secretioninvolve measurement of serumlevels of endogenous substancesnormally secreted in the bile,measurement of secretion of exo-genous substances injected intothe blood, and x-ray, scintigraph-ic, and ultrasonographic visual-izations of the biliary tract.

Plasma levels of both bile saltsand bile pigments are elevated inmany types of hepatobiliary dis-ease. Of these substances, biliru-bin is the most commonly meas-

ured entity. Abnormalities inhepatic function often can be de-tected before the elevation of ser-um bilirubin and the develop-ment of jaundice. This measure-ment is done by intravenouslyinjecting chemicals such assulfobromophthalein and indo-cyanine green. These substancesnormally are taken up andsecreted by the same anionictransport system used for thehepatic secretion of bile pig-ments. Impairment of hepatocytefunction is characterized by aslower than normal disappear-ance of these injected substancesfrom the blood.

Many gallstones are radi-opaque and can be visualized ona plain abdominal x-ray film.Others, however, are radiolucent

and thus are not obvious; radi-opaque dye is required to facilit-ate visualization of these stones.The dye usually consists of iod-inated anions that are taken upand secreted by the anionictransport system of the hepato-cytes. The stones are then sur-rounded by the dye and appearas holes in the contrast medium.Radiopaque dyes are effectiveonly if the anionic transport sys-tem of the hepatocytes is func-tional; therefore, the tests do notwork in the presence of jaundice.Scintigraphy and especially ul-trasound examination are be-coming routine for the confirma-tion or exclusion of gallstone dis-ease. Ultrasonography canprovide information about thethickness of the gallbladder wall,

the presence of intramural gas,and even the diameter of the in-trahepatic and extrahepatic bileducts.

Summary1. Bile is secreted by the liver as a complexmixture of bile acids, phospholipids, choles-terol, bile pigments, electrolytes, and water.2. Primary bile acids are synthesized fromcholesterol by the hepatocytes and are conjug-ated to taurine and glycine. Conjugated bileacids are amphipathic and, along with phos-pholipids and cholesterol, form mixed mi-celles in aqueous solution at pH values foundin the intestine. Micelles take part in the di-gestion and absorption of dietary lipids andlipid-soluble substances.3. Hepatic bile secretion depends primarilyon the secretion of bile acids. Bile acid secre-tion in turn depends on hepatocyte uptakeof bile acids from the portal blood and onbile acid synthesis. Bile secretion depends to alesser degree on electrolyte secretion by hep-atocytes and ductule cells.

4. During the fasting state, most secreted bileis stored in the gallbladder, where electro-lytes and water are absorbed, thus concen-trating the bile acids as an isosmotic micellarsolution. Small amounts of bile empty intothe duodenum during the MMC.5. During the fed state, the gallbladder con-tracts, thereby expelling larger quantities ofbile into the duodenum. Gallbladder con-traction mostly results from the action ofCCK released from the upper intestine in re-sponse to food products.6. In the intestine, some bile acids are decon-jugated, and some primary bile acids are de-hydroxylated to form secondary bile acids.These, along with the still-conjugatedprimary bile acids, are absorbed from the in-testine either passively along the length ofintestine or actively through an Na+-coupledtransport process in the ileum. Once ab-sorbed into the portal circulation, bile acidsare returned to the liver, where they are act-ively absorbed by an Na+-coupled transport

process, conjugated (if need be), andresecreted. Bile acids lost into the feces arereplaced by new synthesis. This pattern ofbile acid secretion, absorption, and resecre-tion is termed the enterohepatic circulation.

KEY WORDS ANDCONCEPTSBileBile acidsMicellesCritical micellar concentrationPhospholipidsCholesterolBile pigmentsInorganic ionsGallbladderEnterohepatic circulationLiverHepatocytesBilirubinHemoglobinBile acid–dependent secretion

Bile acid–independent secretionBile ductSphincter of OddiCholecystokininJaundiceObstructionBacterial infectionsGallstones

Suggested ReadingsDawson, P., Bile formation and the enterohepatic cir-

culationJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 2. San Diego: El-sevier, 2012.

Mawe, G. M., Lavoie, B., Nelson, M. T., Pozo, M. J.,Neuromuscular function in the biliary tractJohn-son, L. R., eds. Physiology of the GastrointestinalTract, ed 5, vol 2. San Diego: Elsevier, 2012.

Moseley, R. H., Bile secretionYamada, T., Alpers, D.H., Laine, L., et al, eds. Textbook of Gastroentero-

logy, ed 3, vol 1. Philadelphia: Lippincott Willi-ams & Wilkins, 1999.

Scharschmidt, B. F., Bilirubin metabolism, bile forma-tion, and gallbladder and bile duct functionSleis-enger, M. H., Fordtran, J. S., eds. GastrointestinalDisease, ed 5, vol 2. Philadelphia: Saunders, 1993.

Wolkoff, A. W., Mechanisms of hepatocyte organicion transportJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 2. San Diego: El-sevier, 2012.

1 1

Digestion andAbsorption ofNutrients

Object ives

Indicate the sources, types, and functionsof the primary digestive enzymes.Explain the transport processes and thepathways involved in the absorption of nu-trients.Describe the processes involved in the di-gestion and absorption of carbohydrates.

Indicate problems that may result in themalabsorption of carbohydrates.Describe the digestion and absorption ofproteins.Explain the role of trypsin in protein diges-tion and how it may be involved in the de-velopment of pancreatitis.Understand the significance of carriers fordipeptides physiologically and clinically.Discuss the processes involved in the di-gestion and absorption of the various lipidsincluding the roles of micelles and chylo-microns.Discuss disorders that may lead to steat-orrhea (excessive fat in the stool).

Motility and secretion are regulated to en-sure the efficient digestion of food and ab-sorption of nutrients across the mucosa of

the gastrointestinal (GI) tract. This chapterexplains how food is broken down into smallabsorbable molecules and how theseproducts are transported into the blood.

Structural-FunctionalAssociationsFood assimilation takes place primarily in thesmall intestine and is aided by anatomicmodifications that increase the luminal sur-face area—Kerckring’s folds, villi, and mi-crovilli. The microvilli are prominent on theapical surface of columnar epithelial cells orenterocytes and occur to a lesser extent ongoblet cells. Collectively the microvillous re-gions constitute the brush border.

Several cell types make up the intestinalepithelium. Students of digestive and ab-sorptive physiology are most familiar withenterocytes and goblet cells. Enterocytesfunction in digestion, absorption, and secre-tion. Goblet cells secrete mucus. The functionof mucus is not clear but may be related tophysical, chemical, and immunologic protec-tion. Both enterocytes and goblet cells are de-

rived from a common stem cell within the in-testinal crypts. Enterocytes and goblet cellsbecome differentiated as they move upwardfrom the base of the crypt, and their charac-teristics are expressed more strongly as theymigrate farther up the villus. As they reachthe tip of the villus, the cells are extrudedand become a component of the succus en-tericus. Following division of the stem cells,some daughter cells migrate to the base ofthe crypt where they differentiate intoPaneth cells, which are part of the mucosaldefenses against infection. These cells secreteseveral agents that destroy bacteria (lyso-zymes and defensins) or produce inflammat-ory responses (tumor necrosis factor-α[TNF-α]).

In humans, the time needed to replace theentire population of epithelial cells (the cellturnover time) is 3 to 6 days. Cell prolifera-tion, differentiation, and maturation are in-fluenced by GI hormones, growth factors,other endocrine substances, and the nature

of the material in the lumen. These processesare also altered by starvation, irradiation,and the loss of a portion of the bowel. Therapid proliferative rate of the intestinal mu-cosa makes it vulnerable to radiation andchemotherapy, procedures used to treat can-cer. Despite the interplay between a basicdynamic process and the extrinsic factorsthat affect epithelial development, undernormal conditions the mucosal appearanceremains relatively constant.

DigestionDigestion is the chemical breakdown of foodby enzymes secreted by glandular cells in themouth, chief cells in the stomach, and the exo-crine cells of the pancreas, or enzymes boundto the apical membranes of enterocytes. Al-though some digestion of carbohydrates, pro-teins, and fats takes place in the stomach, thefinal breakdown of these substances occurs inthe small intestine.

The enzymes important in digestion aresummarized in Figure 11-1. Luminal or cavi-tal digestion results from enzymes secretedby the salivary glands, stomach, and pan-creas. Significant chemical degradation offood is also carried out by hydrolytic enzymesassociated with the small intestinal brush bor-der. Hydrolysis by these enzymes is termedcontact or membrane digestion. Membrane di-gestion is a more acceptable term, because con-tact digestion connotes activity by exogenous

enzymes that become adsorbed on the epi-thelial surface. Membrane digestion refers tohydrolysis by enzymes synthesized by epi-thelial cells and inserted into the apicalmembrane as integral components. The half-life of membrane-bound enzymes (e.g., oli-gosaccharidases) is shorter than that of theepithelial cells. Thus breakdown and resyn-thesis occur several times during the life of asingle cell.

FIGURE 11-1 Source of the principal lu-minal and membrane-bound digestive en-zymes.

Digestion and absorption of essentially allmajor dietary products take place in thesmall intestine. Despite the degradation ofcolonic contents by bacteria, physiologicallyimportant digestion does not occur in thecolon. Nonetheless, absorption in this organis impressive. A practical illustration is thatsome medications administered as rectalsuppositories are systemically functional.During periods of health the principal sub-stances absorbed from the colon are waterand electrolytes. However, life is possiblewithout this organ, as evidenced by patientswho thrive after colectomy.

AbsorptionAlthough the brush border is the site of activ-ity for a number of digestive enzymes, it isalso the barrier that must be traversed by nu-trients, water, and electrolytes on the way tothe blood or lymph. The terms transport andabsorption often are used interchangeably tomean the movement of materials from the in-testinal lumen into the blood. Secretion im-plies movement in the opposite direction.

Mucosal MembraneConceptually the plasma membrane of the en-terocyte is often considered the only factorrestricting the free movement of substancesfrom the gut lumen into the blood or lymph.However, transmural movement actuallytakes place over a complex pathway. This isconveyed schematically in Figure 11-2 and in-cludes (1) an unstirred layer of fluid, (2) the

glycocalyx (“fuzzy coat”) covering the mi-crovilli, (3) the cell membrane, (4) the cyto-plasm of the enterocyte, (5) the basal or later-al cell membrane, (6) the intercellular space,(7) the basement membrane, and (8) themembrane of the capillary or lymph vessel.

FIGURE 11-2 Mucosal barrier. Solutesmoving across the enterocyte from the in-testinal lumen to the blood must traverse anunstirred layer of fluid, a glycocalyx, the ap-ical membrane, the cytoplasm of the cell,the basolateral cell membrane, the base-ment membrane, and finally the wall of thecapillary of the lymphatic vessel. Microvilliare morphologic modifications of the cellmembrane that comprise the brush border.The importance of this region in the diges-tion and absorption of nutrients is depictedby the enlarged microvillus, which illustratesthe spatial arrangement of enzymes andcarrier molecules.

Transport ProcessesAn outstanding property of the enterocytemembrane is its capacity to control the fluxof solutes and fluid between the lumen andblood. This process involves several mech-anisms. Pinocytosis occurs at the base of mi-crovilli and may be a major mechanism inthe uptake of protein. Other uptake pro-cesses include passive diffusion, facilitateddiffusion, and active transport. In the caseof passive diffusion, the epithelium behaveslike an inert barrier, and the particles tra-verse this cell layer through pores in the cellmembrane or through intercellular spaces.Lipid-soluble substances can diffuse throughlipid portions of the membrane. The tightjunction between apposing enterocytes (seeFig. 11-2) forms a mechanical seal that pre-vents mixing of interstitial fluid with lumin-al contents. This seal, however, is relativelyleaky to ions and water in certain regions of

the intestine, thus allowing some exchangebetween the lumen and intercellular spaces.

Adaptation of Digestiveand AbsorptiveProcessesAlterations in intestinal functions in responseto a variety of factors are well documented.Functional adjustments that maintain homeo-stasis or allow an animal to cope better withits environment are termed adaptations. Thequality and degree of adjustment depend onthe type of environmental stimulus en-countered. Clinical situations in which the ca-pacity to adapt is magnified are small bowelresection and bypass. Until recently physi-cians knew only that a patient subjected toone of these operations underwent an initialphase of undernutrition, steatorrhea, andacidic diarrhea and that these symptoms ten-ded to be alleviated with time. Relief fromthe symptoms is believed to be attributable

to adaptations. For example, after proximalbowel resection or bypass, the remainingsegment undergoes hyperplastic changes ac-companied by enhancement of particular ab-sorptive and digestive functions. Adaptationis limited in some circumstances. This pointis illustrated by the fact that the carrier-me-diated absorption of vitamin B12 and bilesalts is confined strictly to the terminalileum. Other regions of the GI tract cannotcompensate if the absorptive capacity forthese compounds in the ileum is lost.

With certain genetic abnormalities, such aslactase deficiency, the capacity to adapt islost. Lactase deficiency and also pancreaticand intestinal diseases of varied origin con-tribute to maldigestion and malabsorption.

CarbohydrateAssimilationPrincipal Dietary FormsThe average daily intake of carbohydrates,which account for approximately 50% of thecalories ingested, is approximately 300 g inthe United States. Starch comprises approx-imately 50% of the total, sucrose approxim-ately 30%, lactose 6%, and maltose 1% to 2%.Trehalose, glucose, fructose, sorbitol, cellu-lose, hemicellulose, and pectins make upmost of the remainder. Starch is a high-molecular-weight compound consisting oftwo polysaccharides, amylose and amylopec-tin. Amylose is a straight-chain polymer ofglucose linked by α-1,4-glycosidic bonds. Therepeating disaccharide unit is maltose.Amylopectin, a plant starch, is the major formof carbohydrate in the diet and is similar to

amylose; however, in addition to 1,4- link-ages there is a 1,6- linkage for every 20 to 30glucose units. Glycogen is a high-molecular-weight polysaccharide similar to amylopec-tin in molecular structure but having con-siderably more 1,6-linkages. Maltose and tre-halose are dimers of glucose in 1,4- and 1,1-linkages, respectively. Sucrose is a disacchar-ide consisting of 1 mole (mol) of glucosebound at the number 1 carbon to the number2 carbon of fructose. Lactose is 1 mol ofgalactose bound at the number 1 carbon tothe number 4 carbon of glucose in a β-link-age.

DigestionLuminal digestion of starch begins in themouth with the action of salivary α-amylaseand ends in the small intestine through theaction of pancreatic α-amylase, which is 94%homologous to salivary amylase. Humansalivary and pancreatic amylases have op-

timum activities near neutral pH and are ac-tivated by chloride (Cl–). Although salivaryamylase is destroyed by acid in the stomach,some enzymatic activity occurs within a bol-us of food while it remains unmixed withacid in the orad stomach. Most starch diges-tion, however, occurs in the small intestine.Hydrolysis occurs not only in the lumen butalso at the surface of epithelial cells becausesome amylase is adsorbed to the brush bor-der.

Amylase attacks only the interiorα-1,4-bonds of amylose, thus yieldingmaltose and the trisaccharide maltotriose.Hydrolysis of amylopectin and glycogenyields similar products in addition to α-limitdextrins ( Fig. 11-3). The latter are oligosac-charides of glucose, formed because theα-1,6- linkages and the α-1,4- bonds near the1,6- linkages are resistant to amylase. Asmuch as one third of amylopectin cannot behydrolyzed by amylase. The average α-limitdextrin contains 5 to 10 glucose residues and

is rapidly hydrolyzed by membrane-boundenzymes.

FIGURE 11-3 Products of starch hydrolys-is by α-amylase.

Products of amylase action on starch andother major dietary sugars are hydrolyzedby brush border carbohydrases. The processbegins with the removal of α-limit dextrins( Fig. 11-4). Glucoamylase is the most activeenzyme, but sucrase and isomaltase alsocleave these bonds. The glucose residues areremoved sequentially from the nonreducingends until a 1-6 branch point is reached. Thisbond is hydrolyzed by isomaltase, which

also is called α-dextrinase. Sucrase cleaves100% of sucrose to yield glucose andfructose. All lactose is broken down intoglucose and galactose by lactase. Trehalasebreaks the α-1,1- bonds of trehalose intoglucose. Sucrase, lactase, and trehalase breakdown sucrose, lactose, and trehalose, re-spectively. Thus the only products of sugardigestion are glucose, galactose, andfructose.

FIGURE 11-4 Summary of carbohydratedigestion. Circled numbers denote the ap-proximate percentage of substrate hydro-lyzed by a particular brush border enzyme.The same carrier actively transports glucoseand galactose into the cell, whereasfructose is absorbed by facilitated diffusion.

Sucrase and isomaltase occur together as amolecular complex. The finding that congen-ital deficiencies of sucrase and α-dextrinase

occur together reveals a close functional re-lationship between these two enzymes. Inhumans, sucrase-isomaltase is a compoundmolecule, one unit with absolute specificityfor sucrose and one for the α-1,6- linkage ofan α-limit dextrin.

In general the small intestine has a largedisaccharidase reserve, so much that therate-limiting step in sugar assimilation is notdigestion but the absorption of free hexosesfollowing hydrolysis. Under normal circum-stances the major portion of sugar assimil-ation is complete in the proximal jejunum.The human GI tract does not possess cellu-lase capable of digesting the β-glucose bondsof cellulose and hemicellulose. These carbo-hydrates account for the undigestible fiberpresent in the diet.

Absorption Of DigestionProductsFor the body to use food-derived monosac-charides, they must be absorbed. Figure 11-5shows how glucose absorption from the in-testine occurs by passive as well as activeprocesses. Although aqueous channels arepresent between enterocytes and pores inbrush border membranes, dietary hexosesare too large to penetrate the membranes inany significant degree by passive diffusion.In humans, the major routes of absorptionare via three membrane carrier systems:SGLT-1, GLUT-5, and GLUT-2.

FIGURE 11-5 Absorption rates of glucosefrom a solution perfused through the intest-ine of a guinea pig. In the absence of oxy-gen, the rate of mediated uptake is propor-tional to concentration. When oxygen isavailable for cellular respiration, the uptakeis greater, and the carrier system can be en-ergized for active transport. mM/L, mil-limoles/liter; mM/hr, micromoles/hour. (Modi-

fied from Ricklis E, Quastel JH: Effects of cations on sugar

absorption by isolated surviving guinea pig intestine. Can J

Biochem Physiol 36:348-362, 1958.)

Fructose is transported by facilitated diffu-sion. The carrier involved is GLUT-5, whichis located in the apical membrane of the en-terocyte. The transport process does not de-pend on either sodium (Na+) or energy.Fructose exits the basolateral membrane byanother facilitated diffusion process in-volving the GLUT-2 transporter. GLUT-2also is responsible for the exit of glucose andgalactose from the absorbing cell.

The carrier systems for fructose and gluc-ose and/or galactose differ insofar as thefructose carrier cannot be energized for act-ive transport, whereas the glucose carriercan. Glucose and galactose are absorbed bysecondary active transport via an Na+-de-pendent carrier system (SGLT-1) ( Fig. 11-6).Mutual inhibition of glucose or galactosetransport by the presence of the other indic-

ates that they are transported by a commoncarrier.

FIGURE 11-6 Summary of a sodium(Na+)-dependent carrier system for glucose-galactose (SGLT-1). Absorption involves therapid movement from lumen to blood by anentry step and exit step mediated by twoseparate carrier molecules with specificityfor hexose. The system is energized by anadenosine (ATP)-dependent Na+ pump thatmaintains an Na+ gradient favoring the entryof 2 Na+ into the cell, with the concomitant

cotransport of glucose or galactose (G).When Na+ is pumped from the cell, moreNa+ and glucose are transported into thecell from the lumen. A carrier (GLUT-2) inthe basolateral membrane facilitates the exitof fructose, as well as glucose andgalactose, from the cell. The transport capa-city of GLUT-2 appears to equal that in-volved in hexose entry, because hexosedoes not accumulate within the cells to asignificant degree. K+, potassium.

The glucose entry step depicted in Figure11-6 involves a carrier that binds Na+ andgalactose or glucose molecules; 2 Na+ foreach glucose or galactose molecule are trans-ported into the cell. The entry step is onlyslightly reversible because of removal of in-tracellular Na+ by the pump on the basolat-eral membrane. Energy input (adenosine tri-phosphate [ATP]) drives the Na+ pump andmaintains an Na+ gradient favoring glucoseentry. Inhibition of the Na+, potassium (K+)-ATPase with specific chemicals (such as ou-

abain) or interference of cellular energy pro-duction leads to cytosolic accumulation ofNa+ and the abolition of active sugar trans-port. The exit of glucose from the cytosol intothe intracellular space is attributed partly todiffusion but mostly to facilitated diffusionvia an Na+-independent carrier located at thebasolateral membrane; this carrier has speci-ficity for all three hexoses (GLUT-2).

Regulation Of AbsorptionThe capacity of the human small intestine toabsorb free sugars is enormous. It has beenestimated that hexoses equivalent to 22pounds of sucrose can be absorbed daily.There appears to be little physiologic controlof sugar absorption. However, chemorecept-ors and osmoreceptors in the proximal smallintestine control the motility and emptyingof the stomach through a negative feedbackprocess mediated by hormones and neuralreflexes. As an example, a volume of isotonic

citrate solution of 750 mL that is placed inthe human stomach passes into the smallbowel in 20 minutes. The volume deliveredin the same time is reduced if sucrose orglucose is added to the citrate solution. Theamount delivered is related inversely to thesugar concentration.

Abnormalities In CarbohydrateAssimilationIt is obvious from the foregoing considera-tions that polysaccharides and oligosacchar-ides are absorbed as monosaccharides. Car-bohydrates remaining in the intestinal lu-men increase the osmotic pressure of the lu-minal contents because of defects in diges-tion and absorption. Bacterial fermentationof these carbohydrates in the lower small in-testine and colon adds to this osmotic effect.The osmotic retention of water in the lumenleads to diarrhea, bloating, and abdominalpain.

Diarrhea caused by the poor assimilationof dietary carbohydrates is most commonlycaused by deficiencies in carbohydrate-split-ting enzymes in the intestinal brush border.Lactase deficiency, the most frequently ob-served congenital disaccharidase deficiency,can exist in the absence of any other intestin-al malfunction. The inability to digest lactoseis actually a developmental change. In fact,a large percentage of the individuals of mostraces, other than those originating in North-ern Europe, will lose lactase activity later inlife. Intolerance of sucrose and isomaltose isa rare disease found primarily in children.Intolerance of maltose has not been docu-mented. The observation that lactase defi-ciency is a relatively common genetic dis-ease, whereas maltase deficiency is not, maybe related to the finding that only one en-zyme displays significant lactase activity, al-though several display activity againstmaltose (see Fig. 11-4). Thus maltose intol-erance would require the simultaneous ab-

sence of all enzymes possessing maltaseactivity. Maldigestion of starch in humansis nonexistent because pancreatic amylase issecreted in tremendous excess.

Intolerance to glucose and galactose hasbeen documented in rare instances. In thesecases the patients thrive and show no symp-toms when they are fed fructose. The explan-ation for this is found in the specificity ofsugar absorption. Glucose and chemicallyrelated sugars are absorbed by an Na+-de-pendent secondary active transport process,whereas fructose is absorbed by Na+-inde-pendent facilitated diffusion. Thus in thesepatients, the SGLT-1 transporter is absent,whereas GLUT-5 is present.

Besides defects in carbohydrate assimila-tion caused by the congenital or acquiredenzyme deficiencies, assimilation of dietarysugars may be impaired by diseases of theGI tract. Celiac disease, certain bacterial in-fections, and some protozoan and helminthinfections are associated with inflammation

and structural derangements in the smallbowel mucosa. These conditions are often at-tended by brush border enzyme deficienciesand hexose malabsorption ( Fig. 11-7). It isnot uncommon to find lactase deficiency as along-term consequence of intestinal diseasebecause this enzyme is present in the intest-ine at low levels compared with maltase andsucrase.

FIGURE 11-7 Relative rates of absorptionof fructose and glucose in an equimolar mix-ture studied by an intubation technique in acontrol subject (A), a patient with glucosemalabsorption (B), and a patient with celiacdisease (C). (From Dahlquist A: In Sipple HL, McNutt

KW (eds): Sugars in Nutrition. New York, Academic Press,

1974.)

Symptoms of osmotic diarrhea includecramps and abdominal distention. An oraltolerance test can be used to diagnose dis-accharidase deficiency if this is a suspected

cause. After an overnight fast, adult patientsare fed 50 g of lactose in a 10% aqueous solu-tion (children are usually fed 2 g/kg of bodyweight). Blood samples are taken for glucoseanalysis before and at 5, 10, 15, 30, 45, and60 minutes after lactose administration. Anincrease in blood glucose of at least 25 mg/dL over fasted levels indicates normal hy-drolysis of lactose and normal absorption ofthe glucose product. A flat lactose tolerancecurve or failure to observe a rise in bloodglucose to more than 25 mg/dL followinglactose ingestion indicates low lactase activ-ity. A value between 20 and 25 mg/dL isquestionable. In this case the test may be re-peated or, if laboratory facilities permit, in-testinal biopsy specimens can be collectedand examined for enzyme activity. In deal-ing with biopsy specimens, enzyme activityusually is expressed as units per gram of tis-sue protein. Tolerance tests for disaccharidesother than lactose are seldom performed, buta similar procedure would suffice. Glucose

or galactose tolerance tests should be per-formed to exclude monosaccharide malab-sorption as the cause of a flat lactose toler-ance curve.

Protein AssimilationDigestionThe daily dietary intake of protein varies con-siderably in different parts of the world.People from Eastern countries, who eat ahigh-carbohydrate diet in the form of rice,consume less protein than those from meat-eating Western societies, where a typical dietcontains more than 100 g per day. Secretionsfrom the salivary glands, stomach, pancreas,and intestines along with sloughed cells addanother 40 g protein per day, which is diges-ted and absorbed in the same manner as diet-ary protein.

Protein digestion begins in the stomachwith the action of pepsin. The enzyme pre-cursor pepsinogen is secreted by chief cells inresponse to a meal and low gastric pH. Acidin the stomach is responsible for activatingpepsinogen to pepsin. Three pepsin isozymes

have been recognized. All have a pH op-timum of 1 to 3 and are denatured abovepH 5. Pepsin is an endopeptidase with spe-cificity for peptide bonds involving aromaticL-amino acids.

Pepsin activity terminates when the gast-ric contents mix with alkaline pancreaticjuice in the small bowel. Chyme in the in-testine stimulates the release of secretin andcholecystokinin (CCK), which in turn, alongwith cholinergic nerve activity, cause thepancreas to secrete bicarbonate and enzymesinto the intestinal lumen.

The two general classes of pancreatic pro-teases are endopeptidases and exopepti-dases. The basis of classification and the par-ticular characteristics of specific enzymes be-longing to each class are given in Table 11-1.

TABLE 11-1Principal Pancreatic Proteases

Pancreatic proteases are secreted into theduodenum as inactive precursors. Trypsino-gen, which lacks proteolytic activity, is ac-tivated by enterokinase, an enzyme locatedon the brush border of duodenal enterocytes.The exact chemical composition of enterok-inase is not known; however, the fact that themolecule is 41% carbohydrate probably pre-vents its rapid digestion by proteolytic en-zymes. The activity of enterokinase is stimu-lated by trypsinogen, and it is released fromthe brush border membrane by bile salts. En-terokinase activates trypsinogen by releasinga hexapeptide from the N-terminal end ofthe precursor molecule ( Fig. 11-8). Activetrypsin, once formed, acts autocatalyticallyin the manner of enterokinase to activate thebulk of trypsinogen. Trypsin also activatesother peptidase precursors from the pan-creas (see Fig. 11-8). Chymotrypsinogen isactivated by cleavage of the peptide bondbetween arginine and isoleucine, which arethe fifteenth and sixteenth amino acid

residues at the N-terminus. Although struc-tural rearrangement occurs, no peptide frag-ment is released because of a disulfide bondbetween the cysteine residues at positions 1and 122 in the protein chain. This configur-ation is the active form of chymotrypsino-gen. Cleavage at other points in thechymotrypsinogen molecule produces othermolecular species of chymotrypsin havingrelatively little physiologic importance. Theexact mechanism for activation of proelast-ase is not known, and activation of proc-arboxypeptidases A and B is relatively com-plicated, involving proteolysis of at least twoproenzymes.

FIGURE 11-8 Activation of pancreatic pro-teolytic enzymes. The process begins in thelumen when enterokinase cleaves ahexapeptide from trypsinogen and convertsit to the active enzyme trypsin.

Once in the small intestine, pancreatic en-zymes undergo rapid inactivation becauseof autodigestion. Trypsin is the enzymeprimarily responsible for inactivation.

Development Of PancreatitisIn developed countries, 80% of the cases ofacute pancreatitis are the result of either bil-iary stone disease or ethanol abuse. Alcoholconsumption is the major cause of chronicpancreatitis.

As pointed out previously, trypsin playsa central role in the activation of other pan-creatic zymogens. Normally trypsin remainsas inactive trypsinogen until it is secreted in-to the duodenal lumen. The mechanisms re-sponsible for the intracellular activation oftrypsin are not totally clear. One hypothesisstates that it is catalyzed by lysosomal hy-drolases after the colocalization of these hy-drolases with digestive zymogens within

membrane-bound organelles during theearly stages of pancreatitis.

Premature activation of trypsinogen with-in the pancreas initiates the entire activationcascade of other proteases, results in autodi-gestion of pancreatic cells, and causes acutepancreatitis. The body has several mechan-isms to prevent premature trypsin activa-tion. These include synthesis of pancreatictrypsin inhibitors, isolation of zymogensfrom lysosomes, and a site on trypsin thatis susceptible to digestion by trypsin itself.Thus when trypsin comes into contact withother trypsin molecules, it is able to cleavethem and irreversibly inactivate the enzyme.

This site for autodigestion is an arginineresidue in position 117. Research has locateda single guanine-to-adenine gene mutationthat results in the substitution of histidinefor arginine (R117H). This substitution pre-vents trypsin from being inactivated andwas discovered in several families of pa-tients with hereditary pancreatitis. Thus this

mutation eliminates one of the failsafe mech-anisms preventing the premature activationof trypsinogen and is the basis for at leastone form of hereditary pancreatitis.

Absorption Of DigestionProductsMembrane digestion and absorption areclosely related phenomena in protein assim-ilation, and physiologists have been occu-pied by two fundamental questions concern-ing them: (1) In what form do products ofproteolysis cross the brush border mem-brane of the epithelial cell? (2) In what formdo these products leave the cell to enter theblood?

L-Isomers of some amino acids are ab-sorbed by carrier-mediated mechanisms inmuch the same manner as glucose is ab-sorbed. As with glucose, the cell entry pro-cess requires Na+ as part of a ternary com-plex (see Fig. 11-6), and uphill transfer oc-

curs by secondary active transport. Otheramino acids and some of those absorbed byactive transport can also be absorbed by fa-cilitated diffusion processes that do not re-quire Na+ ( Table 11-2). A new class of elec-trogenic proton-dependent amino acid trans-porters—PAT proteins—has been cloned.Present on the apical membrane, PAT pro-teins transport short-chain amino acids (gly-cine, alanine, serine, proline) into the cell,along with a hydrogen ion (H+). Thus theentry of the amino acid is coupled with themovement of a proton down its electrochem-ical gradient.

TABLE 11-2Carrier Systems for the Transport ofAmino Acids

Certain L-amino acids compete with oneanother for uptake by intestinal cells. Studiesof competition have led to the recognition

of several different carrier systems for aminoacid absorption (see Table 11-2). There islittle doubt that the absorption of free aminoacids by gut mucosa is physiologically im-portant. However, amino acids appear inportal blood faster and reach a higher levelwhen peptides from an acid hydrolysate ofprotein contact the gut mucosa than whenthere is an equimolar solution of free aminoacids ( Fig. 11-9). Moreover, greater amountsof total nitrogen are absorbed from a solu-tion of trypsin hydrolysate of proteins thanfrom an equivalent solution of amino acidsin free form. Competition for transportbetween two chemically related amino acidsis not observed when the same two acids areabsorbed after ingestion of their dipeptidesand tripeptides. In addition, the site in theintestine for the maximum absorption ofamino acids in small peptide form is differ-ent from that for the absorption of freeamino acids. The absorptive capacity fordipeptides and tripeptides is greater in the

proximal intestine, whereas the capacity forabsorbing single amino acids is greater in thedistal intestine. The current explanation ofthese findings is that a separate carrier sys-tem for small peptides is involved in absorp-tion. For example, free glycine absorption re-quires an amino acid carrier system. If satur-ation of the system occurs under physiologicconditions, the maximum rate of uptake be-comes limiting. If, however, a second carri-er for dipeptides or tripeptides of glycine ispresent, the amino acids can enter the cell insmall peptide form. Thus two separate sys-tems for glycine entry exist and work in aparallel manner.

FIGURE 11-9 Jejunal rates of glycine andleucine absorption (mean ± SEM, five sub-jects) from perfusion of test solutions con-taining either L-glycyl-L-leucine or an

equimolar mixture of free L-glycine and freeL-leucine. (From Adibi SA: Intestinal transport of

dipeptides in man: relative importance of hydrolysis and in-

tact absorption. J Clin Invest 50:2266-2275, 1971.)

The prevailing concepts regarding proteinassimilation are illustrated in Figure 11-10.Luminal digestion of a protein meal pro-duces approximately 20% free amino acidsand 80% small peptides. As with the freeacids, dipeptides and tripeptides resultingfrom digestion can be absorbed intact by acarrier-mediated process. However, tet-rapeptides, pentapeptides, and hexapeptidesare poorly absorbed; instead they are hydro-lyzed by brush border peptidases to freeamino acids or smaller absorbable peptides.Small peptides are absorbed by a carrierwith broad specificity. This transport processis independent of the Na+ gradient and isstimulated by an inwardly directed H+ gradi-ent. The acidic microclimate pH that nor-mally exists on the luminal surface of the

brush border membrane provides the driv-ing force for the peptide transport system.This is referred to as the H+/peptide cotrans-porter (PEPT1), and it is functionallycoupled to the Na+/H+ exchanger, NHE3, inthe same membrane.

FIGURE 11-10 Summary of the digestionand absorption of protein. Luminal digestionyields 20% free amino acids and 80% pep-tides consisting primarily of two to six aminoacid residues.

Peptides that enter enterocytes are hydro-lyzed by cytoplasmic peptidases to aminoacids. These, in turn, diffuse or are moved

by carrier-mediated processes from the in-tracellular compartment, across the basolat-eral membrane, into the blood. As is the casewith the apical membrane, several differentcarriers exist in the basolateral membrane(see Table 11-2). Some of these also are Na+

dependent. A few peptides enter the bloodintact, and this may explain why certain bio-logically active peptides exert their effectswhen they are given orally.

Abnormalities In ProteinAssimilationPancreatic insufficiency caused by variousdiseases, including cystic fibrosis and hered-itary pancreatitis, may be associated with adecrease or absence of trypsin and may leadto poor digestion of protein. Cases ofprimary proteinase deficiency caused bycongenital trypsinogen deficiency have beenreported. In those patients, chymotrypsinand carboxypeptidase activities are lacking

also, because trypsin cannot be formed to ac-tivate the precursors of these pancreatic pro-teases.

Intestinal malabsorption and the failure toreabsorb certain amino acids in the proximalrenal tubule occurs in some hereditary dis-eases, thus providing evidence that the car-riers are identical in the two tissues. Cys-tinuria is characterized by defective trans-port of the cationic amino acids (arginine,lysine, and ornithine) and cystine in the kid-ney and the small bowel ( Fig. 11-11). Theintestinal malabsorptive condition is of littleor no consequence in the disability producedby cystinuria, given that the affected aminoacids are absorbed as small peptides.However, the disease is severe becausecystine has low solubility in water, and asthe urine is concentrated in the distal neph-ron, cystine precipitates and forms stones.Hartnup’s disease is a hereditary conditionin which the active transport of neutralamino acids is deficient in both the renal tu-

bule and the small intestine. An interestingfinding is that, although neutral amino acidsare not absorbed, they readily appear in theblood after ingestion of their dipeptides.This is compelling evidence that absorptionof the dipeptides of certain amino acids isthe result of a completely separate processfrom the one involved in the transport offree amino acids. These patients lose signi-ficant amounts of amino acids in their urine,and the condition may become significant inthose whose dietary protein intake is low.Because tryptophan is a neutral amino acid,patients with Hartnup’s disease suffer fromniacin deficiency (pellagra); approximately50% of the vitamin is synthesized from thisamino acid. Tryptophan is also the precursorfor the neurotransmitter serotonin, and itsdecreased synthesis may contribute to theneurologic symptoms associated with thisdisease.

FIGURE 11-11 Jejunal absorption of freearginine and leucine during perfusion ofsolutions containing L-arginine (1 mM) andL-leucine (1 mM) or L-arginyl–L-leucine (1mM). Results are from studies carried out insix normal subjects and six cystinuric pa-tients. (From Silk DBA, Dawson AM. In Crane RK,

Guyton AC (eds): International Review of Physiology. III:

Gastrointestinal Physiology. Baltimore, University Park

Press, 1979.)

Lipid AssimilationDietary fats comprise the most concentratedsource of calories ingested by humans, and in-take varies considerably in different culturesdepending on the proportion of meat in thediet. Dietary lipids include such substancesas triacylglycerides, fat-soluble vitamins (A,D, E, and K), phospholipids, sterols, hydro-carbons, and waxes that compose cell wallsor membranes of plants and/or animals. Theprinciples of lipid assimilation are dealt withthrough a consideration of triglycerides,phospholipids, and sterols. The propensity oflipids to form ester linkages and the insolubil-ity of lipids in water make their digestion andabsorption a complex process. Unlike carbo-hydrates and proteins, lipids enter epitheli-al cells by a sequence of chemical and phys-ical steps that render water-insoluble molec-ules capable of being absorbed by passive dif-fusion. The process depends on four major

events: (1) secretion of bile and variouslipases, (2) emulsification, (3) enzymatic hy-drolysis of ester linkages, and (4) the solubil-ization of lipolytic products within bile saltmicelles.

DigestionFat assimilation begins in the stomach,where food (partially digested by pepsin) ischurned into a coarse mixture and is re-leased in small portions into the duodenum.Except for short-chain fatty acids, no absorp-tion of fat from the stomach occurs. A pro-cess, controlled through the action of CCK,slows gastric motility and emptying whenfat is in the small intestine. CCK also stim-ulates the pancreas to secrete lipase andcauses contraction of the gallbladder. Onefunction of bile salts released into the duo-denum is to perpetuate the emulsification offat droplets by decreasing the surface ten-sion at the oil-water interface. An emulsifica-

tion is a suspension of fat droplets held apartby phosphatidylcholine (lecithin), bile salts,fatty acids, and other emulsifying agents.The emulsified fat droplets are approxim-ately 1 micrometer (µm) in diameter. Theemulsification process is important to in-crease the surface area of lipids in prepara-tion for their enzymatic hydrolysis and is be-gun by the churning action of the stomach,which breaks contents into small droplets.

Enzymes from three sources are involvedin the digestion of dietary lipids. These en-zymes are food-bearing lipases, gastriclipase, and pancreatic lipases.

Enzymes that digest dietary lipids can befound in food per se (e.g., acid lipases, phos-pholipases). These enzymes may function inautodigestion, a process aided by the acidenvironment of the stomach. Human milkcontains a lipase identical in chemical prop-erties to bile salt–stimulated lipase secretedby the pancreas. Known as carboxyl esterlipase (CEL), it is active against cholesterol

and vitamin A esters. CEL also hydrolyzesglycerol esters of long-chain fatty acids atthe physiologic pH of the small bowel. Afeature that distinguishes this esterase fromwell-known pancreatic lipase is that the lat-ter has pronounced specificity for the 1 and3 ester bonds of triglycerides, whereas CELshows no positional specificity. Despite thelack of a clear functional role, it is presumedthat CEL is important to the use of milk lip-ids in newborn infants, who have a low in-testinal bile salt concentration and absorbglycerol and free fatty acids better thanmonoglycerides. This presumption is com-patible with knowledge that CEL is stablebetween pH 3.5 and 9 and is broken downonly slowly by pepsin. Thus most of the en-zyme would pass through the infant’s stom-ach without denaturation. The fact that CELrequires bile salts for activation suggests thatit is not functional until it reaches the smallintestine.

Lipolytic activity in the human stomach isprimarily the result of gastric lipase secretedby cells of the corpus and fundus. This en-zyme has an acidic pH optimum, rangingfrom 3 to 6. Gastric lipase acts primarily atthe outer ester linkages, thus producing fattyacids and diglycerides. Pancreatic lipase isnormally produced in great excess, and theabsence of gastric lipase would not alter fatdigestion. However, the contribution of gast-ric lipase can be significant in newborns andpatients with pancreatic lipase deficiency orinactivation, such as could occur inZollinger-Ellison syndrome because of theacid environment of the duodenum.

Pancreatic lipase-colipase, phospholipaseA2, and cholesterol esterase (nonspecificlipase) are secreted by the pancrease andfunction within the intestinal lumen.

Pancreatic lipase, or glycerol ester lipase,is secreted in an active form, rather than asa precursor enzyme. It displays optimumactivity at pH 8, remains active down to pH

5, and is denatured at pH 3.5—irreversiblyso at pH 2.5. Although bile salts inhibit itsenzymatic activity, this is prevented underphysiologic circumstances by the combina-tion of lipase with colipase. Colipase, a poly-peptide (102 to 107 amino acids) secreted bythe pancreas along with lipase in a 1:1 ratio,is secreted as procolipase that is activatedwhen hydrolyzed by trypsin to a peptidecontaining 96 amino acids. Whereas lipase-colipase complexes are scarce within theduodenum during fasting, the presence offat stimulates the secretion of these compon-ents in large quantities. The inactivation oflipase by bile salts results from the capacityof bile salts to displace lipase at the fatdroplet–water interface, where it must exertits action. Colipase prevents inactivation byanchoring lipase to the oil-water interface inthe presence of bile salts. Once colipase at-taches to the fat droplet, lipase binds to aspecific site on the colipase molecule in a 1:1ratio and consequently carries out its cata-

lytic function, breaking down triglycerides.Colipase also has the capacity to bind to abile salt micelle. Therefore, the products offat hydrolysis need diffuse only a short dis-tance to a micelle. Thus, despite its name,colipase has no enzymatic activity of its own.

Lipase is secreted in large excess and rap-idly hydrolyzes triglycerides. The enzymeshows positional specificity. It cleaves the 1and 3 ester linkages, yielding free fatty acidsand 2-monoglycerides. That only smallamounts of free glycerol are produced re-flects the lack of action against the 2 esterlinkages ( Fig. 11-12).

FIGURE 11-12 Positional specificity ofpancreatic lipase.

Phospholipase A2 is secreted as a proen-zyme and is activated by trypsin in much thesame fashion as trypsinogen is converted toits active form (i.e., through cleavage of sev-eral amino acids from the N-terminus). Bilesalts and phospholipids form mixed micellesthat become substrates for phospholipase A2.The enzyme requires bile salts for optimalactivity in hydrolyzing dietary phospholip-ids at the 2 position and producing lyso-phospholipid and free fatty acids.

Human pancreatic cholesterol esterasehydrolyzes not only cholesterol esters butalso the esters of vitamins A, D, and E andthose of glycerides. In contrast with pancre-atic lipase, cholesterol esterase hydrolyzesall three ester linkages of triglycerides. Thiscapacity accounts for its name—nonspecificesterase. Cholesterol esterase is activeagainst substrates that have been incorpor-ated into bile salt micelles. Activity appar-ently depends on the presence of specific bilesalts. The enzyme in humans attacks cho-lesterol ester in the presence of taurocholateand taurochenodeoxycholate and is prob-ably identical to CEL (previously discussed).

Absorption Of LipolyticProductsIn addition to the function just mentioned,bile salts perform an important function inthe actual absorption of lipolytic products.Sodium glycocholic and taurocholic acids,

which are major bile salts, have both hydro-phobic and hydrophilic portions. When theirconcentration in the intestine is raised to acritical level, bile salt monomers form water-soluble aggregates called micelles. The con-centration of bile salt at which molecular ag-gregation occurs is referred to as the criticalmicellar concentration. Conjugated bilesalts have a lower critical micellar concentra-tion than do unconjugated bile salts. Where-as emulsion particles are 2000 to 50,000 ang-stroms (Å) in diameter, mixed micelles areapproximately 30 to 100 Å in diameter, witha hydrophilic outer surface and a hydro-phobic center. In addition, although emul-sion particles form a suspension, micelles arein true solution. The water-insolublemonoglycerides from lipolysis are solubil-ized within the hydrophobic center of themicelle ( Fig. 11-13). In turn, fatty acids, lyso-phospholipids, cholesterol, and fat-solublevitamins may be solubilized. A mixed mi-cellar solution is water clear. Micellar solu-

bilization is important because it enhancesthe diffusion of poorly soluble dietary lipidsthrough the unstirred aqueous layer overly-ing the enterocytes.

FIGURE 11-13 Solubilization of nonpolarlipid by a bile acid–polar lipid micelle. (Modi-

fied from Hoffman AF, French A, Littman A: Syllabus: Di-

gestion and Absorption. Chicago, American Medical Asso-

ciation, 1975.)

Two forms of evidence support the par-ticipation of micelles in the assimilation offatty substances. First, mixed micelles (bilesalts plus lipids) are found in the intestine.Second, long-chain fatty acids and monogly-

cerides are absorbed more rapidly from mi-cellar solutions than from emulsions.

One possible mechanism of lipid uptakeby enterocytes is the absorption of the entiremixed micelle. This proposed mechanism isnot accepted, however, because variouslipolytic products are absorbed at differentrates. In addition, because most bile salts areabsorbed in the ileum and lipid absorptionusually is completed in the midjejunum, it isunlikely that the whole micelle enters the in-testinal epithelium.

The importance of micellar solubilizationlies in the ability of micelles to diffuse acrossthe unstirred water layer and present largeamounts of fatty acids and monoglyceridesto the apical membrane of the enterocyte.The brush border membrane is separatedfrom the bulk solution in the intestinal lu-men by the unstirred water layer. Singlefatty acid and monoglyceride molecules, be-ing poorly soluble in water, move slowlythrough this barrier. Because uptake de-

pends on the number of molecules in contactwith the enterocyte membrane, their absorp-tion is diffusion limited. By contrast, micellesare water soluble, diffuse readily throughthe unstirred layer, and increase the concen-tration of fatty acids and monoglycerides atthe membrane by 100- to 1000-fold. An acid-ic microclimate exists next to the plasmamembrane that protonates fatty acids,thereby assisting in their release from the mi-celle and promoting their flux across the ap-ical membrane. Thus mixed micelles keepthe intestinal water layer saturated with fattyacids, and absorption proceeds at an optimalrate. Short- and medium-chain fatty acids donot depend on micelles for uptake becauseof their higher solubility in and diffusionthrough the unstirred aqueous layer.

Until recently, it was thought that all fatdigestion products were absorbed by simplediffusion. However, current evidence indic-ates a carrier protein-dependent process.Some products such as linoleate show satur-

able uptake. Uptake in some cases exhibitsa specificity that cannot be explained bysimple diffusion. The relative contribution ofthe protein mediated component to total up-take by enterocytes is unclear and is likely tobe small.

Intracellular EventsMonoglycerides and free fatty acids ab-sorbed by enterocytes are resynthesized intotriglycerides by two different pathways: themajor pathway, monoglyceride acylation,and the minor pathway, phosphatidic acidacylation ( Fig. 11-14).

FIGURE 11-14 Summary of the digestionand absorption of triglyceride. Monogly-cerides and long-chain fatty acids enter thecells after first being incorporated into mi-celles. Glycerol and short- and medium-chain acids, because of their solubility in theaqueous unstirred layer, enter without mi-celle solubilization.

Monoglyceride AcylationPathwayThe monoglyceride acylation pathway in-volves the synthesis of triglycerides from2-monoglycerides and coenzyme A (CoA)-activated fatty acids. Acyl-CoA synthetase isthe enzyme that acylates fatty acids. The en-zymes monoglyceride and diglyceride acyl-transferases are responsible for catalyzingthe formation of diglycerides and trigly-cerides, respectively. The enzymes involvedin this pathway are associated mainly withthe smooth endoplasmic reticulum.

An interesting aspect of intracellulartriglyceride synthesis is that certain fattyacids are used in preference to others. Thisoccurs despite similar rates of absorption byenterocytes and similar rates of enzymaticCoA activation and glyceride esterification.These observations have been explained bythe presence of intracellular fattyacid–binding proteins (FABPs), which haveaffinities for fatty acids of different chainlengths and varying degrees of saturation.Such proteins exert their influence after ab-sorption occurs and before esterificationtakes place.

A current theory on how FABPs operatepresumes that absorbed fatty acids bindstrongly to the apical membrane of entero-cytes. Solubilization is brought about whenthe fatty acids bind specifically with recept-ors on FABPs. This facilitates the transfer ofthe free fatty acids from the apical mem-brane to the smooth endoplasmic reticulum,where esterification into diglycerides and

triglycerides takes place. This process is par-ticularly effective in the intracellular transferof long-chain fatty acids. By binding long-chain fatty acids and 2-monoglycerides,FABPs maintain the concentration gradientfor diffusion of these molecules into themembrane and protect the cell from highconcentrations of fatty acids that would becapable of solubilizing lipid membranes.Such a situation could occur during the di-gestion of a lipid meal. Short- and medium-chain fatty acids, which show less affinityfor the cell membrane, are water soluble andnot bound by specific proteins. Instead theyleave the cell in free form and enter the blooddirectly, rather than as reesterified trigly-ceride in chylomicrons.

Phosphatidic Acid PathwayTriglycerides also can be synthesized fromCoA-activated fatty acids and α-glycero-phosphate. The latter is formed from phos-

phorylated glycerol or from the reduction ofdihydroxyacetone phosphate derived fromglycolysis. One mole of α-glycerophosphateacylated with 2 mol of CoA–fatty acidsyields phosphatidic acid, which is dephos-phorylated to form diglyceride, which inturn is acylated to form triglyceride. Thisminor pathway for triglyceride synthesis inthe intestine is termed the phosphatidic acidpathway.

Phosphatidic acid may also be importantin the synthesis of phospholipids such asphosphatidyl choline, ethanolamine, andserine. Alternatively, phospholipids can bederived from acylation of absorbed lyso-phospholipids by appropriate acyltrans-ferases. The acylation of lysophosphatidylcholine forms phosphatidyl choline, which isused in the formation of chylomicrons.

Dietary cholesterol is absorbed in freeform. However, a major fraction leaves theepithelial cells in chylomicrons as esters offatty acids. This finding is indicative of the

highly active intracellular reesterificationprocess. The ratio of free to esterified choles-terol in intestinal lymph is influenced by theamount of cholesterol in the diet (low dietarycholesterol favors the cellular exit of great-er amounts of free sterol in chylomicrons). Inhumans the percentage of net cholesterol ab-sorption decreases as the dietary content in-creases.

Chylomicrons are lipoprotein particlesapproximately 750 to 5000 Å in diameter thatare synthesized within enterocytes and existin the form of an emulsion. Although theirchemical composition may vary slightly de-pending on size, chylomicrons are approx-imately 80% to 90% triglycerides, 8% to 9%phospholipids, 2% cholesterol, 2% protein,and traces of carbohydrate. Studies suggesthow triglycerides and esterified cholesteroland fat-soluble vitamins (which form thecore) become coated with apolipoprotein,phospholipid, and free cholesterol (whichmake up the surface of the chylomicron).

Synthesis of the chylomicron appears to be atwo-step process. Small particles containingapolipoprotein B and a small mass of corelipids are synthesized in the rough endoplas-mic reticulum. Microsomal triglyceridetransfer protein (MTP) is responsible foradding lipids to apolipoprotein B. Concur-rently, triglyceride-rich particles that lackapolipoprotein B are synthesized in the lu-men of the smooth endoplasmic reticulum.The two particles join, forming a nascentchylomicron, also called a prechylomicron.This complex is too large to cross the mem-brane of the smooth endoplasmic reticulum.This is accomplished by a specialized endo-plasmic reticulum–to-Golgi transport vesiclecalled the prechylomicron transport vesicle(PCTV). Following transport to the Golgi ap-paratus, the prechylomicron acquires apoli-poprotein A1 and is glycosylated. The newlyformed chylomicrons are secreted by exocyt-osis into the interstitial space and enter thegaps between the endothelial cells that make

up the lacteals. Chylomicrons are too large toenter the pores of blood capillaries.

It is evident that apolipoprotein synthesisby epithelial cells and its incorporation intochylomicrons are essential for fat absorption.Inhibition of protein synthesis causes largeamounts of triglyceride to accumulate intra-cellularly. Several apolipoproteins—termedA, B, C, and E—have been identified in in-testinal lymph. Apolipoprotein B is similarimmunologically to plasma very-low-dens-ity lipoprotein (VLDL) and low-density lipo-protein (LDL) but chemically and physicallyshows some uniqueness. It has been sugges-ted that VLDL in plasma may representchylomicrons of varying densities. The roleof apolipoproteins in fat absorption andmetabolism remains an area of active invest-igation.

Abnormalities In LipidAssimilationImpaired lipid assimilation is considered un-der the general title of malabsorption. Inmost cases, all nutrients are malabsorbed tosome extent. However, the clinical entity isdefined in terms of fat malabsorption be-cause, unlike carbohydrates and proteins, fatnot absorbed in the small intestine passesthrough the colon and appears in the feces ina measurable form.

The presence of excessive fat in the stool,steatorrhea, can be established by extractingfecal samples with organic solvents and de-termining the total fatty acids present, ex-cluding volatile short-chain acids. Less than7 g of fecal fatty acid per day is normal. Val-ues greater than this level suggest malab-sorption or the carcinoid syndrome.

A convenient way to consider fat malab-sorption is to review the various steps in as-similation and consider possible derange-

ments in each. For each derangement, atleast one possible disease has been recog-nized:

Disorders of gastric mixing and intestinalmotility do not have any clear-cut disease as-sociation, although malabsorption may fol-low the rapid gastric emptying that accom-panies partial gastrectomy. In addition, rap-id intestinal transit has been suggested as thebasis for diarrhea in hyperthyroidism.

Luminal digestion of triglycerides may bederanged by defects in pancreatic enzymesecretion or action. A quantitative defectwould be caused by impaired enzyme syn-thesis and secretion, as occurs with cysticfibrosis (a congenital disease of exocrineglands) or chronic pancreatitis. Normal di-gestion can proceed with as little as 5% to10% of normal enzyme secretion. A qualit-ative defect would occur if the conditionsfor enzyme action were not optimal (as ingastric acid hypersecretion [Zollinger-Ellis-on syndrome], when the pH of the duodenal

contents is lowered and lipase cannot func-tion or may even be denatured). A defect inpancreatic lipase results in the presence oftriglycerides in the stool.

Transport from the lumen is a special stepin fat absorption and depends on a suitablebile acid concentration, which may be lowbecause of a quantitative bile acid deficiencythat occurs with an interrupted enterohepat-ic circulation (e.g., ileal resection or dysfunc-tion, biliary obstruction, or cholestatic liverdisease). There may be a qualitative deficitof the bile acids in a condition known as thebacterial overgrowth syndrome (in which stas-is in the upper intestine leads to bacterialovergrowth, with deconjugation of bile acidsby the bacteria). Free bile acids are absorbedpassively in the jejunum because they arelargely un-ionized at the duodenal pH. Bileacids need to be ionized to form micelles.Therefore, the un-ionized state leads toimpairment of fat absorption as well as im-paired absorption of cholesterol and fat-sol-

uble vitamins. Bile acid deficiency does notinterfere with digestion, so in this case freefatty acids and monoglycerides appear in thestool.

Mucosal cell transport is, of course, neces-sary for all nutrients, but it is of particularimportance in fat absorption because the ab-sorbed fatty acids or monoglycerides mustbe reconstituted to triglycerides and thenformed into chylomicrons. No disease hasbeen associated with triglyceride synthesis;however, there is a disease of inadequatechylomicron formation called abetalipopro-teinemia. This condition is caused by a failureto synthesize MTP, which is necessary forthe initial steps that bring apolipoprotein Btogether with triglyceride in the process ofchylomicron formation. The synthesis ofapolipoprotein B is in fact normal in affectedpersons, so the condition is misnamed.

Lymphatic transport is necessary for theabsorption of fat that has been reconstitutedto chylomicrons. This step is defective in two

rare diseases, congenital lymphangiectasiaand Whipple’s disease.

Thus, by considering the steps in fat ab-sorption, it is possible to predict the diseasesthat can lead to malabsorption. Steatorrhea,which attends malabsorption, can be allevi-ated to a large degree by diets containingtriglycerides of medium- rather than long-chain fatty acids. The explanation for the be-nefit of this dietary maneuver is that glycerolesters of medium-chain fatty acids are hy-drolyzed faster than are ester linkages in-volving long-chain fatty acids. Medium-chain fatty acids are water soluble and canbe absorbed from aqueous solution. In addi-tion, they are transported directly into portalblood without involvement of chylomicrons.

VitaminsVitamins are organic compounds that cannotbe manufactured by the body but are vital formetabolism. They are considered (in this in-stance) not on the basis of any physiologicfunction, but rather on the basis of whetherthey are water soluble or fat soluble ( Table11-3). This feature is emphasized becausetheir solubility dictates the general mechan-ism by which vitamins are absorbed.

TABLE 11-3Solubility of Vitamins

Vitamin Fat Sol-uble

Water Sol-uble

A +B1 (thiamine) +B2 (riboflavin) +Niacin +C (ascorbic acid) +D +E +K +Folic acid +B6 (pyridoxine, pyridoxal, pyri-doxamine)

+

B12 +Pantothenic acid +Biotin +

Water-soluble vitamins are represented byan array of compounds. The principles thatapply to the absorption of hexoses andamino acids apply to the absorption of vit-

amins as well. Strongly ionized or high-molecular-weight compounds are absorbedpoorly compared with nonionized, low-molecular-weight substances.

Relatively little information exists regard-ing the processes involved in the intestinaluptake of vitamins. Most evidence suggeststhat passive diffusion is the predominantmechanism. Exceptions exist for thiamine,vitamin C, folic acid, and vitamin B12, forwhich special transport mechanisms havebeen reported.

At low luminal concentrations, thiamine(vitamin B1) can be absorbed in the jejunumof some species, including humans, by anNa+-dependent, active process, whereas athigh concentrations, passive diffusion pre-dominates. The presence of a carrier-medi-ated transport system is suggested by thefinding that metabolic inhibitors, thiamineanalogues, and the absence of Na+ all de-press thiamine uptake by enterocytes. Ribo-flavin (vitamin B2) is absorbed in the proxim-

al small bowel by facilitated transport. Pyri-doxine (vitamin B6) is absorbed by simplediffusion.

Vitamin C is required in only a few spe-cies, including humans. Humans are capableof absorbing it from the intestine by passiveprocesses and also by active transport (anenergy-dependent process, requiring Na+).In rats and hamsters, species that do not re-quire ascorbic acid, uptake of the vitamin oc-curs only by passive mechanisms.

Folic acid has been reported as beingtransported actively in the duodenum andjejunum of humans and from the entire smallintestine of some rodents. A mediated pro-cess may be predicted from two facts: folicacid is a strongly electronegative compound(with a molecular weight of 441), and un-couplers of respiration (hence energy pro-duction) interfere with its absorption.

Vitamin B12 (cobalamin) absorption re-quires intrinsic factor, a glycoproteinsecreted by the parietal cell of the gastric mu-

cosa. Binding of intrinsic factor to dietaryvitamin B12 is necessary for attachment tospecific receptors located in the brush borderof the ileum. Initially cobalamin is releasedfrom foods by food preparation and expos-ure to light. It is then recognized by the co-balamin binding protein, haptocorrin (a gly-coprotein), which in humans is secreted insaliva and is resistant to digestion by acidand pepsin. Thus haptocorrin protects in-trinsic factor during its transit through thestomach. In the duodenum, the haptocorrinis digested by pancreatic enzymes, and thevitamin then forms a complex with intrinsicfactor that is resistant to digestion. The pres-ence of calcium (Ca2+) or magnesium (Mg2+)and an alkaline pH are necessary for optimalattachment of the intrinsic factor–B12 com-plex to the receptor, a process that does notrequire energy. The actual uptake of B12 ispresumed to be by pinocytosis; however,this point is not clear. Any disease conditionthat interferes with the production or secre-

tion of intrinsic factor or with the attachmentof the intrinsic factor–B12 complex to its re-ceptor in the ileum leads to malabsorption ofvitamin B12.

The fat-soluble vitamins (A, D, E, and K)depend on solubilization within bile salt mi-celles for intestinal absorption. Vitamin A,or retinol, is ingested as β-carotene and ab-sorbed as such. Once in the enterocyte, β-carotene is cleaved intracellularly into tworetinol molecules. Esters of dietary vitaminsD and E, as noted earlier in this chapter, aredigested by cholesterol ester hydrolase be-fore their solubilization in micelles. Dietaryvitamin K (K1) is absorbed in the intestine byan active transport system, whereas bacteri-ally derived K2 is taken up passively fromthe lumen. Except for retinol, which is rees-terified, the fat-soluble vitamins appear inexocytosed chylomicrons biochemically un-altered by metabolic processes within the en-terocyte. The chylomicrons are then ex-truded into the lymphatics and transported

via the thoracic duct into the blood. Thus theabsorption of fat-soluble vitamins dependson the absorption of dietary lipids. In fact, afatty meal is necessary for absorption of reas-onable amounts of vitamin E. Defects lead-ing to fat malabsorption result in deficienciesof fat-soluble vitamins.

Abnormality In VitaminAbsorptionPernicious anemia occurs when the bodydoes not make enough red blood cells be-cause of malabsorption of vitamin B12. Themost common cause is the failure to secretesufficient intrinsic factor, which is usuallythe result of atrophic gastritis and the ab-sence of parietal cells. This is an autoimmunecondition, and the body produces parietalcell antibodies that destroy the intrinsicfactor–secreting parietal cells. In rare in-stances pernicious anemia can be caused bythe absence of pancreatic proteases and the

failure of intrinsic factor to be released fromhaptocorrin so that it cannot bind vitaminB12. Surgical removal of the ileum also res-ults in pernicious anemia because that is theonly site of vitamin B12 absorption. The liverstores a 3- to 5-year supply of vitamin B12, sopatients do not show symptoms of the condi-tion until several years after it develops. Thecondition is treated by vitamin B12 injections.

Summary1. Digestion is the chemical breakdown offood by enzymes secreted into the lumen ofthe gut and those associated with the brushborder of enterocytes.2. All physiologically significant absorptionof nutrients occurs in the small intestine, themucosal surface of which is greatly increased,thus providing a large area for uptake.3. The major luminal breakdown of carbohy-drates is catalyzed by amylase. Breakdown ofremaining glucose polymers and other disac-charides is carried out by specific enzymesin the brush border membrane. Glucose andgalactose share an Na+-dependent, secondaryactive transport mechanism for absorption.4. The major enzymes involved in the luminaldigestion of protein are secreted in inactiveforms by the pancreas and are then activatedby trypsin following its own activation by en-terokinase.

5. Dipeptides, tripeptides, and amino acidsare absorbed across the brush border mem-brane by a variety of transport processes.Larger peptides are broken down into theseabsorbable forms by peptidases associatedwith the brush border. Absorbed small pep-tides are hydrolyzed to amino acids withinthe cytoplasm, and almost all absorbed pro-tein leaves the enterocyte in the form ofamino acids.6. Fat droplets are suspended in an emulsi-fication by the action of lecithin, bile salts,peptides, and other such agents. Colipasedisplaces a bile salt molecule from the fat-water interface, thereby allowing pancreaticlipase to digest the triglycerides. Pancreaticlipase is essential to fat digestion and pro-duces 2-monoglycerides and free fatty acids.7. The breakdown products of fat digestionare solubilized in micelles by bile salts andother amphipathic molecules. Micelles dif-fuse through the unstirred layer, and fat di-gestion products are absorbed from the mi-

celles at the enterocyte brush border mem-brane.8. Within the enterocyte, triglycerides andphospholipids are resynthesized and pack-aged into chylomicrons that contain apopro-tein on their surface. Chylomicrons are exo-cytosed into the intercellular space. Toolarge to enter capillaries, the chylomicronsenter lacteals and eventually reach the bloodvia the thoracic lymph duct.

KEY WORDS ANDCONCEPTSBrush borderEnterocytesGoblet cellsPaneth cellsDigestionLuminal/cavital digestionContact/membrane digestionUnstirred layer of fluidGlycocalyxPassive diffusion

Facilitated diffusionActive transportStarchSteatorrheaSucroseLactoseMaltoseAmylopectinLactase deficiencyEndopeptidasesExopeptidasesTrypsinogenEnterokinaseChymotrypsinogenProelastaseProcarboxypeptidases A and BTriglyceridesPhospholipidsSterolsEmulsificationCarboxyl ester lipaseGastric lipase

Pancreatic lipaseColipasePhospholipase A2

Cholesterol esteraseNonspecific esteraseMicellesCritical micellar concentrationEnterohepatic circulationFatty acid–binding proteinsChylomicronsApolipoprotein

Suggested ReadingsAhnen, D. J. Nutrient assimilation. In: Kelly W. N.,

ed. Textbook of Internal Medicine. Philadelphia:Lippincott, 1989.

Ganapathy, V., Protein digestion and absorp-tionJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 2. San Diego: El-sevier, 2012.

Hamilton, R. L., Wong, J. S., Cham, C. M., et al.Chylomicron-sized lipid particles are formed inthe setting of apolipoprotein B deficiency. J LipidRes. 1998; 39:1543–1557.

Mansbach, C. M., II., Abumrad, N. A., Enterocytefatty acid handling proteins and chylomicronformationJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 2. San Diego: El-sevier, 2012.

Milne, M. D. Hereditary disorders of intestinal trans-port. In: Smythe D. H., ed. Intestinal Absorption.New York: Plenum Press, 1974.

Said, H. M., Nexo, E., Mechanism and regulation ofintestinal absorption of water-soluble vitamins:cellular and molecular aspectsJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

Tso, P. Intestinal lipid absorption. In Johnson L. R.,ed. : Physiology of the Gastrointestinal Tract, ed 3,New York: Raven Press, 1994.

Wellner, D., Meister, A. A survey of inborn errors ofamino acid metabolism and transport in man. An-nu Rev Biochem. 1980; 50:911–968.

Whitcomb, D. C. Hereditary pancreatitis: new in-sights into acute and chronic pancreatitis. Gut.1999; 45:317–322.

Wright, E. M., Sal-Rabanal, M., Loo, D. D. F.,Hirayama, B. A., Sugar absorptionJohnson, L. R.,eds. Physiology of the Gastrointestinal Tract, ed 5,vol 2. San Diego: Elsevier, 2012.

1 2

Fluid and ElectrolyteAbsorption

Object ives

Indicate the sources of fluid and electro-lytes in the GI tract and their sites of ab-sorption.Describe the mechanisms involved in andthe location of the sites for the absorptionof sodium, potassium, chloride, bicarbon-ate, and water.Understand the mechanism and signific-ance of the intestinal secretion of fluid andelectrolytes.

Explain the difference between osmoticand secretory diarrheas and discuss thedisorders that may lead to each.Discuss the basic steps involved in theabsorption of calcium and iron and howeach is regulated.

Minerals and water enter the body throughthe intestine and provide the solutes andsolvent water for body fluids. The electro-lytes of primary importance include sodium(Na+), potassium (K+), hydrogen ion (H+), bi-

carbonate ( ), chloride (Cl−), calcium(Ca2+), and iron (Fe2+). Each of these ions hasone or more mechanisms by which it istransported across the intestinal epithelium.This chapter considers these mechanismsand their relationship with water absorptionand secretion.

Bidirectional Fluid FluxDuring a 24-hour period, 7 to 10 L of waterenters the small intestine ( Fig. 12-1). Fluid de-rived from food and drink accounts for ap-proximately 2 L. The other 7 L is derived fromthe secretions of the gastrointestinal (GI) tract:saliva, 1 L; gastric juice, 2 L; pancreatic juice,2 L; bile, 1 L; and small intestinal secretions,1 L. Of the amount entering, only approxim-ately 600 mL per 24-hour period reaches thecolon, a finding indicating that most water isabsorbed in the small intestine. Because theaverage daily fecal weight is approximately150 g, of which 100 g is water, 500 mL of fluidis absorbed daily from the colon. This volumerepresents 10% to 25% of the absorptive ca-pacity of the colon, which can absorb approx-imately 4 to 6 L of fluid per day. Malabsorp-tion of solutes and water in the small intestinemay permit enough fluid to enter the colon tooverwhelm its absorptive capacity and cause

diarrhea. This, in turn, can precipitate severeelectrolyte deficiencies. Although it is pos-sible that ions and water may be added tothe feces from colonic mucosa, the majorsource of water and electrolytes in a diarrhe-ic stool is the small intestine (see Fig. 12-1).

FIGURE 12-1 Volume and composition offluid entering and leaving the gastrointestin-al tract during 24 hours. The locations of thevarious ion transporters are shown alongwith the volume and composition of the fluidleaving the small intestine and the colon.

Cl−, chloride; H+, hydrogen ion; ,bicarbonate; K+, potassium; Na+, sodium.

It is evident from the foregoing accountthat several liters of fluid are secreted intothe GI tract daily, and several liters are ab-sorbed. The volume of fluid moving fromblood to lumen (secretion) is less than thatmoving from the lumen to the blood (ab-sorption), thus resulting in net absorption.Absorption generally results from the pass-ive movement of water across the epithelialmembrane in response to osmotic and hy-drostatic pressures. Because of these so-called Starling forces, the consequent bulkflow of fluid is analogous to the flow of fluidacross capillary walls. In the absence of food,

ions are the most important contributors toosmotic pressure in the intestinal lumen. Theionic composition of the luminal contentsmay vary along the length of the intestineand is different from that in feces. Luminalfluid generally remains isotonic withplasma, however, because of the relative per-meability of the mucosal membrane. Thecontinued production of solutes by colonicbacteria, together with the relative imper-meability of the colonic membrane to water,usually causes stool water to be hypertonic,350 to 400 milliosmoles (mOsm)/L, toplasma.

Ionic Content of LuminalFluidOsmotic equilibration with plasma of materi-al entering the small bowel occurs rapidly inthe duodenum. Water is absorbed from hy-potonic solutions and enters hypertonic solu-tions. Na+ and Cl− also leave hypertonic solu-tions. Most of this movement occurs throughthe relatively permeable junctions betweenthe epithelial cells of the proximal small in-testine.

Proceeding from the duodenum to thecolon, the Na+ and Cl− concentrations in thelumen progressively become lower than theplasma concentrations. In the duodenum, theconcentration of Na+ is approximately 140mEq/L, equal to the serum concentration. Themajor anion is Cl−. Na+ concentrations de-crease in the jejunum and reach approxim-ately 125 mEq/L in the ileum. The major an-

ions in the ileum are Cl− and . Na+

decreases to 35 to 40 mEq/L in the colon,whereas the K+ concentration increases to 90mEq/L, up from 9 mEq/L in the ileum. Themajor anions in the colon are Cl− and

.These values indicate an effective absorp-

tion process for Na+ that becomes increas-ingly efficient toward the distal portions ofthe gut. This is caused in part by a decreasein the permeability of the epithelium thatprevents the back-diffusion of ions absorbedin the distal portions. Whereas the absorp-tion of Na+ in the distal gut is effective, theconservation of Cl− is even more so. Cl− is ex-

changed for metabolically derived .K+ is absorbed passively by the small in-

testine as the volume of intestinal contentsdecreases. The concentration of K+ remainsroughly equal to that in the serum (4 or 5mEq/L). In the colon, net K+ secretion occurs.

Because of K+ secretion and the exchange of

Cl− for in the colon, prolongeddiarrhea results in hypokalemic metabolicacidosis.

Transport Routes andProcessesIons move between the gut lumen and theblood through transcellular and paracellularpathways. The passive movement of Na+,both into and out of the lumen, is largelythrough the lateral spaces. This movement isdetermined by the tight junctions or zonulaeoccludens. The rate of this passive compon-ent is affected by electrochemical gradientsand Starling forces. Normally these forces aresmall and account for only a small fractionof the net transport. They can, however, bealtered under certain conditions, with markedeffects.

The tight junction is about twice as perme-able to Na+ and K+ as it is to Cl−. Thus electric-al potentials can arise across this structure. If,for example, NaCl is moving across the tightjunction, the Cl− will be retarded relative to

the Na+, and the surface toward which themovement is occurring will become positiverelative to the other surface. Ions slightly lar-ger than Na+ and K+ are much more restric-ted in their movement.

The pores through which transcellular dif-fusion takes place are probably larger (7 to8 angstroms [Å]) in the proximal bowel thanin the ileum (3 to 4 Å). This restricts the pass-ive transport of solutes in the distal gut andallows these solutes to exert a more effectiveosmotic pressure. In turn, the reduced per-meability makes carrier-mediated transporta more important contributor to net trans-port out of the lumen.

Sodium-Chloride TransportPhysiologic models describing Na+ and Cl−

absorption in the small intestine are shownin Figure 12-2. Na+ is absorbed from the lu-men across the apical membrane of epithelialcells by four mechanisms. These include the

movement of Na+ by restricted diffusionthrough water-filled channels, the cotrans-port of Na+ with organic solutes (e.g., gluc-ose and amino acids), the cotransport of Na+

with Cl−, and the countertransport of Na+ inexchange for H+. Because Na+-Cl− cotrans-port and Na+-H+ exchange are electricallyneutral processes, the driving force for Na+

to enter the cell is the Na+ concentration dif-ference between the luminal fluid and thecytoplasm. Na+ movement through poresand Na+ cotransport with organic solutes arealso driven by the Na+ concentration differ-ence but are electrogenic and increase thenegative electrical potential across the epi-thelial cell membrane. The contribution ofrestricted diffusion to overall Na+ absorptionis probably small relative to other mechan-isms.

FIGURE 12-2 Mechanism of sodium chlor-ide (NaCl) absorption in the small intestine.Na+ enters passively, following the electro-chemical gradient, by cotransport with nutri-ents such as glucose or amino acids, or byneutral cotransport with Cl− or in exchangefor protons via a countertransport process.Cl− also is absorbed by neutral exchange

with bicarbonate ( ). Na+ exit fromthe cell is via the energy-dependent Na+

pump, and Cl− follows passively. The elec-trical potential difference across the apicalmembrane is –40 mV, and across the entirecell is +2 to +5 mV with reference to the lu-minal side. Ouabain is an inhibitor of Na+,potassium (K+)-adenosine triphosphatase

(ATPase). H+, hydrogen ion; ,carbonic acid.

The presence of these various mechanismsvaries over the length of the small intestine.In the proximal bowel, Na+ is absorbedprimarily coupled to H+ countertransportand solute (amino acids and sugars) cotrans-port. In the ileum, Na+ is absorbed coupledto the absorption of Cl−. Throughout the gut,Cl− is absorbed along the electrical gradient.In the ileum, coupled Na+ transport is themajor carrier-mediated pathway for Cl− ab-

sorption. Exchange of Cl− for occurs

in the distal ileum and increases dramatic-ally in the colon and rectum. This mechan-

ism accounts for the high contentand alkaline pH of stool water.

The Na+-K+ pump on the basolateral mem-branes of the absorbing epithelial cell main-tains both the low intracellular Na+ level andthe negative membrane potential. The Na+

that enters by all four mechanisms describedpreviously is extruded into the intercellularspaces by the Na+ pump, which is the well-known Na+,K+-activated adenosine triphos-phatase (ATPase). This enzyme-carrier mo-lecule is activated by intracellular Na+ andextracellular K+ to split adenosine triphos-phate (ATP), thereby releasing energy. In theprocess, three Na+ ions are pumped out ofthe cell for every two K+ ions pumped intoit. The pumping out of more Na+ than thereis K+ entering creates a potential difference(PD) across the basolateral membrane,which is called an electrogenic potential.

The pump is inhibited by cardiac glycosides(e.g., ouabain). Because Na+ exit from theepithelial cell is coupled with K+ entry, theintracellular K+ concentration is much higherthan the extracellular concentration. Thiscauses the constant, downhill leakage of K+

from the interior to the exterior by K+ chan-nels on the basolateral membranes (i.e., theK+ actively pumped into the cell returns tothe exterior through passive leaks).

The epithelial absorption of Cl− involves,in addition to cotransport with Na+, coun-

tertransport with (see Fig. 12-2).

is produced by a metabolic processwithin the epithelial cells through the hydra-tion of carbon dioxide (CO2) by carbonic an-hydrase. Both absorptive mechanisms moveCl− into the epithelial cell against an elec-trochemical PD. The energy for the uphillmovement of Cl− is derived from the down-hill movement of Na+ into the cell or from the

downhill movement of out of thecell and into the lumen.

Because of the transcellular electrical PD(the serosal side is positive with reference tothe lumen and with reference to the cell in-terior), Cl− is driven passively from the celland into the serosal fluid. In addition, lu-minal Cl− can move through the paracellularpathway into the serosal solution. The mag-nitude of this passive absorptive process isgoverned by the magnitude of the transmur-al PD. That PD is developed through the ac-tion of the Na+-K+ pump and the absorptionof Na+ coupled to organic solutes. It is in-fluenced by the resistance of the paracellularpathway to ion flow. In the small intestine,the relatively leaky epithelium prevents thetransmural PD from rising to more than 2to 5 millivolts (mV). In the colon, where theepithelium is less leaky, the PD is approxim-ately 20 mV. Thus the driving force for Cl−

absorption is greater in the colon.

All regions of the colon absorb Na+ andCl− ( Fig. 12-3). Unlike in the small intestine,however, the cotransport of Na+ with organ-ic solutes is lacking. Restricted diffusion isthe primary mechanism for colonic Na+ ab-sorption. This electrogenic process, whichincreases in activity from oral to aboral re-gions, depends on channels that are underregulation by mineralocorticoids. For ex-ample, aldosterone increases the number ofNa+ channels and enhances Na+ absorption.Na+ in the lumen of the colon also is ab-sorbed through an electroneutral processthat includes Cl− cotransport. This probablyinvolves Na+-H+ countertransport coupled

with Cl−- countertransport, as occursin the small intestine. This secretion of

accounts for the alkalinity of stoolwater.

FIGURE 12-3 Mechanism of ion absorp-tion in the colon. Sodium (Na+) enters pass-ively, whereas chloride (Cl−) enters in neut-

ral exchange with bicarbonate ( ).

Net secretion of potassium (K+) occurs. H+,hydrogen ion.

Potassium TransportDiffusion through paracellular pathways inthe small intestine is the primary mechanismby which K+, derived from the diet or fromsecretions of the upper GI tract, undergoesnet absorption. In the colon (but not in thesmall intestine), the apical and basolateralmembranes are permeable to K+. Thus be-cause of the high concentration of intracellu-lar K+ maintained by the Na+-K+ pump, someK+ leaks passively across the apical mem-brane of epithelial cells. Factors that elevateintracellular K+, such as aldosterone-stimu-lated Na+ absorption, increase K+ secretion.Therefore, aldosterone conserves body Na+

at the expense of K+.

Mechanism for WaterAbsorption andSecretionWater absorption or secretion always occursin response to osmotic forces produced by thetransport of organic solutes or ions and canbe explained in terms of a three-compartmentmodel and local osmotic effects ( Fig. 12-4).In the absorbing intestine, solutes are movedfrom the lumen (first compartment) into andthen out of the epithelial cell. This creates alocal osmotic gradient that causes water tomove from the gut lumen, across the cell, andinto the intercellular space (second compart-ment). The entrance of water increases the hy-drostatic pressure within this space andcauses the bulk flow of water and solutesthrough the basement membrane into capil-laries (third compartment). In the nonabsorb-

ing intestine, the imbalance of forces acrossthe capillary wall leads to filtration of fluidinto the interstitium. However, the capillaryfiltration rate is balanced by lymphaticdrainage. In the secreting intestine, fluid inthe interstitium is attracted osmotically intothe lumen.

FIGURE 12-4 Fluid absorption accordingto the standing osmotic gradient hypothesis.The sum of hydrostatic and osmotic pres-sures in the intraepithelial space, interstiti-um, and capillaries favors fluid absorption.In the nonabsorbing state, fluid filtering fromthe capillaries would be drained by thelymphatics. The attraction of fluid from thecytosol and interstitium secondary to highosmotic pressure in the lumen leads to se-cretion. NaCl, sodium chloride.

Osmotic equilibration and thus absorptionoccur by different means in the duodenumand the ileum. The duodenum functions tobring chyme into osmotic equilibrium withplasma. If a hypertonic solution is placed inthe duodenum, isotonicity is reached by arapid flow of water from blood to lumen,thereby increasing the volume of the originalsolution. More distally, in the small intestine,absorption of solutes creates a gradient forwater absorption. Thus the volume is de-creased because of both solute and water up-

take, and the isotonicity of the luminal solu-tion is maintained during this process. Insummary, the sequence of responses to hy-pertonic contents entering the intestinal lu-men is the following: (1) the dilution causedby osmotic attraction of water from theblood and (2) the movement of fluid fromthe lumen into the blood secondary to thetransport of solutes.

If a hypotonic solution enters the intestine,the flux of water from lumen to blood isgreater than from blood to lumen and leadsto net absorption of fluid. This in turn is fol-lowed by the isotonic uptake of fluid.

The gut normally absorbs all electrolytesand water presented to it and, unlike thekidney, does not appear subject to hour-by-hour homeostatic regulation. Nevertheless,some external regulation occurs. The auto-nomic nervous system has effects on NaCltransport. Adrenergic (α-receptor) or antich-olinergic stimuli tend to increase absorption,but cholinergic or antiadrenergic stimuli

tend to decrease absorption. Other agents(e.g., serotonin, dopamine, the endogenousopiates, enkephalins, and endorphins) altergut transport, usually in the secretory dir-ection. However, the opiates morphine andcodeine increase gut absorption.

The ileum has relatively little ability to re-spond to Na+ depletion and/or mineralocor-ticoids. By contrast, the large intestine issensitive to both these assaults, which can in-crease Na+ absorption and K+ secretion. Min-eralocorticoids can decrease the Na+ concen-tration in fecal water from 30 to 2 mEq/Land increase the K+ concentration from 75to 150 mEq/L. The influence of aldosteroneon Na+ transport is exerted at two points.There is an increase in Na+ permeability ofthe brush border membrane caused by theactivation of new Na+ channels. In addition,aldosterone apparently increases the num-ber of Na+ pump molecules in the basolateralmembrane.

Factors that cause the osmotic retention ofwater in the gut lumen or stimulate fluid se-cretion may lead to diarrhea. Saline laxat-ives such as Epsom salts (magnesium sulfate[MgSO4]) increase fecal water because of theslow and incomplete absorption of poly-valent ions. Disease states such as disacchar-idase deficiency or monosaccharide malab-sorption increase the amount of unabsorbedsolutes entering the colon and cause osmoticdiarrhea.

Intestinal SecretionBoth the small and the large intestines secretewater and electrolytes. This process residesprimarily in the crypt cells and is responsiblefor maintaining a liquid chyme.

The transcellular secretion of Cl− accountsfor most of the secretory activity, and themechanism is illustrated in Figure 12-5. Cl−

enters the cell through a carrier located in thebasolateral membrane. The carrier uses theNa+ gradient established by the Na+,K+-ATPase to move Cl− into the cell against itselectrochemical gradient. Two Cl− are movedinto the cell along with one Na+ and one K+ viathis NaK2Cl cotransporter. The Na+ enteringthe cell is extruded by the Na+ pump, and K+

diffuses back out of the cell through channelsin the basolateral membrane. Cl− enters thelumen through channels in the apical mem-brane, and Na+ moves through paracellular

pathways, driven by the lumen-negative PDcreated by the secretion of Cl−. The resultingsecretion of Na+ and Cl− establishes an os-motic gradient that draws water into the lu-men.

FIGURE 12-5 Model for the secretion ofchloride (Cl−) and sodium (Na+) by the cryptcells of the small and large intestines. A, ag-onist; ATP, adenosine triphosphate; cAMP,cyclic adenosine monophosphate; K+, po-tassium.

The apical membranes of the crypt cellscontain at least two different Cl− channels.One is activated by increases in intracellularCa2+ and is stimulated by acetylcholine re-leased by the enteric nervous system. Theother type is stimulated by agents that in-crease cyclic adenosine monophosphate(cAMP) and is identical to the cystic fibrosistransmembrane conductance regulator(CFTR) that also is found in pancreatic andairway epithelial cells. Agents such as vaso-active intestinal peptide (VIP), secretin, andprostaglandin that stimulate this channel ac-tivate adenylate cyclase to increase cAMP,which in turn activates cAMP-dependentprotein kinase A. Defects in this channel ac-count for the intestinal, pulmonary, and pan-creatic problems associated with cysticfibrosis.

CLINICALAPPLICATIONS

Diarrhea is a major cause ofdeath or disability in the worldtoday, and it affects individualsof all ages. Death is the direct orindirect result of hypovolemiaand circulatory collapse com-pounded by metabolic acidosisand hypokalemia.

Secretion that is stimulated bygastrointestinal hormones andneurotransmitters after a meal isa physiologic aid to digestionand serves to maintain a liquidchyme during the process of ab-sorption. However, excessivechloride (Cl−) secretion, with ac-companying fluid secretion, canbecome pathologic. The resultingsecretory diarrheas are preval-ent in many developing nationsand constitute a leading cause ofdeath. In some instances this dis-

order can result from excessiveblood levels of normal secreta-gogues such as vasoactive intest-inal peptide, which can be pro-duced by certain tumors. In mostcases, however, secretorydiarrhea is caused by infection ofthe gut by pathogenic bacteriasuch as Vibrio cholerae andEscherichia coli. These bacteriaproduce enterotoxins that bindto receptors on the apical mem-branes of crypt cells. Receptorbinding permanently activatesthe adenylate cyclase located onthe basolateral membrane, andthe cell is stimulated to secretemaximally for its lifetime. Hugevolumes of water and electro-lytes may be secreted, so that theabsorptive capacity of the gut isgreatly exceeded. Unless proper

therapy is available, dehydrationand death can result.

The presence of sugars oramino acids in the lumen leads totheir absorption by the sodium-coupled mechanism, which alsoleads to the absorption of a Cl−

to preserve electrical neutrality, atotal of three osmotically activesolutes. This finding led to thesuggestion that orally admin-istered saline solutions contain-ing glucose and amino acidscould reduce salt and water lossfrom secretory diarrheas. Theseoral replacement or rehydrationtherapies have markedly re-duced death and disabilitiesworldwide and especially inareas where cholera is a problem.

The second and more commontype of diarrhea is osmotic

diarrhea, which can have a vari-ety of causes, each of which leadsto the accumulation within thesmall intestine of nonabsorbablesolutes. As discussed earlier, be-cause the small intestine is leakyto water, the luminal contentsare always isotonic to plasma. Itfollows then that the accumula-tion of nonabsorbable, osmotic-ally active solutes will generatean osmotic difference that drawsfluid into the lumen. The absenceof certain enzymes such aslactase, for example, results inthe accumulation of their sub-strates. Inadequate bile salt se-cretion or the inactivation of pan-creatic lipase can cause steator-rhea, which is accompanied bywater loss. Increased rate oftransit of material through the

small bowel may not providesufficient time for absorption. Inthis case the solutes are absorb-able, but they are not in contactwith the absorbing surface longenough. Decreases in the amountof the absorbing surface can alsocause diarrhea as in cases of in-fection, inflammation, or aller-gies, such as gluten-sensitive en-teropathy.

Calcium AbsorptionAbsorption of Ca2+ by enterocytes is an im-portant component in the regulation ofwhole-body Ca2+ ( Fig. 12-6). Thetransepithelial movement of the cation occursagainst an electrochemical potential. The pro-cess, although not entirely known, is localizedin the proximal small intestine. Ca2+ transportoccurs in three major steps. First, Ca2+ absorp-tion involves entry at the brush border mem-brane. Second, a mechanism must be presentto regulate intracellular Ca2+ levels to preventaltered cell function. Third, Ca2+ exit occursat the basolateral membrane. The synthesis ofthe proteins involved in each of these steps isregulated by vitamin D.

FIGURE 12-6 Calcium (Ca2+) absorptionby an enterocyte within a larger scheme ofCa2+ homeostasis. Vitamin D3, 1,25-(OH)2-D3, stimulates Ca2+ transport by interactingwith nuclear receptors to control the syn-thesis of a Ca2+ channel (TRPV6), acalcium-binding protein (calbindin), and theCa adenosine triphosphatase (ATPase).During periods of high intake, Ca2+ is alsoabsorbed paracellularly.

Transport of Ca2+ is initiated by1,25-dihydroxyvitamin D3 (1,25-[OH]2-D3).This active product is derived from vitaminD3 (cholecalciferol) formed in the skin by theaction of ultraviolet radiation on7-dehydrocholesterol. Vitamin D3 is trans-ferred to the liver and converted to 25-OH-D3. The kidney, through a step regulated byparathyroid hormone, converts 25-OH-D3 to1,25-(OH)2-D3. Enterocytes take up the1,25-(OH)2-D3, where it reacts with a recept-or molecule in the nucleus. The transcription

of specific deoxyribonucleic acid (DNA) andprotein synthesis are mandatory steps in theaction of 1,25-(OH)2-D3 on Ca2+ transport.The Ca2+-binding activity of the synthesizedproteins correlates with Ca2+ transport. Pre-sumably at least one Ca2+ channel of the tran-sient receptor potential vanilloid (TRPV)family is inserted into the brush border andfacilitates (gates) the entry of Ca2+ down anelectrochemical gradient.

Once inside the cell, Ca2+ interacts with abinding protein, calbindin, to minimize therise in intracellular free Ca2+. It has been pro-posed, but not substantiated, that the mito-chondria participate in this “buffering” ac-tion. The synthesis of this binding protein isa 1,25-(OH)2-D3–dependent process. Exit ofCa2+ at the basolateral membrane is againstan electrochemical gradient and occurs viathe Ca2+-ATPase, the synthesis of which isalso 1,25-(OH)2-D3–dependent.

Ca2+ absorption is regulated over the longterm by plasma Ca2+ levels. As intestinal ab-sorption of Ca2+ rises, plasma Ca2+ increases;this change inhibits the secretion of para-thyroid hormone. In turn, formation of1,25-(OH)2-D3 in the kidney is inhibited (seeFig. 12-6). A reduction in 1,25-(OH)2-D3

eventually causes Ca2+ absorption to wanebecause the synthesis of new Ca-bindingprotein will cease. At high intake levels, Ca2+

can also be absorbed through the paracel-lular pathway. Although the mechanism ofCa2+ absorption is not a closed issue, themodel depicted in Figure 12-6 provides acurrently accepted working scheme.

Iron AbsorptionAbsorption of iron is regulated by total bodyiron requirements and by the bioavailabilityof iron. Under physiologic conditions, dietaryiron is acquired through transport processesin the proximal small intestine. Although thestomach, ileum, and colon have some capa-city for iron absorption, this process is mostprevalent in the duodenum and jejunum.Normally, because body iron is conserved,absorption of iron by the gut is low comparedwith the amount ingested.

Heme (derived from meat) is an importantdietary source of iron. After it is absorbed in-tact by enterocytes, it loses iron from its por-phyrin ring. Heme is absorbed by endocytosisand digested by lysosomal enzymes to releasefree iron. In all other chemical forms, iron isabsorbed only to the extent to which it can bereleased from food in ionizable form. The in-soluble complexes of iron with food become

more soluble at a low pH. Gastric acid isimportant in solubilizing iron, and patientswith deficient acid secretion absorb less iron.Organic acids such as ascorbic or citric re-duce Fe3+ to Fe2+, which is absorbed moreefficiently. A brush border reductase, duo-denal cytochrome b (DCYTB), plays an im-portant role in reducing ferric to ferrousiron. Nonheme iron represents the largestfraction of dietary iron. The cellular mech-anism of iron transport has not been com-pletely described. However, a working hy-pothesis can be synthesized from what isknown about the influx of iron across thebrush border, its intracellular processing,and its efflux across the basolateral mem-brane of enterocytes into the circulation ( Fig.12-7).

FIGURE 12-7 Inorganic iron (Fe3+) is re-duced to the ferrous form (Fe2+) by the re-ductase, DCYTB, in the apical membraneand is transported into the cell by thedivalent metal transporter, DMT1. Someiron is bound to ferritin and stored within thecell. Cytoplasmic iron is pumped out of thecell via ferroprotein 1 (FPN1), oxidized byhephaestin (HEPH), and bound to transfer-rin (TF) in the interstitial space. H+, hydro-gen ion; K+, potassium; Na+, sodium.

Once reduced, ferrous iron is transportedacross the apical surface by divalent metaltransporter 1 (DMT1). An inward flux of H+,dependent on the outward flux of Na+ estab-lished by the Na+,K+-ATPase, provides thedriving force for the carrier. Within the cell,the fate of the iron depends on the body sup-ply. If body stores are filled, most iron willbe stored within ferritin and lost when theenterocyte is sloughed into the lumen. If ironstores are low, most will cross the basolateralmembrane via the iron export protein fer-

roprotein 1 (FPN1). During the export pro-cess, iron is oxidized for binding to transfer-rin (TF) in the interstitial fluid and plasma.Oxidation is carried out by the iron oxidasehephaestin (HEPH), which is expressed inthe basolateral membrane.

The uptake pathway for heme is not un-derstood in detail, but the HCP1 receptoris probably involved. Heme can be brokendown in lysosomes and the iron released forexport, or it can exit the cell intact and bebound to hemopexin for distribution to thebody.

The body requirement for iron influencesintestinal uptake. Absorption is thought tobe regulated at a minimum of two sites. First,during iron deficiency, transcription factorsare activated that enter the enterocyte nuc-leus and increase the synthesis the enzymeDCYTB and the iron transporter, DMT1. Se-cond, the amount of the storage protein, fer-ritin, is also regulated. The formation of fer-ritin is least when the body iron levels are

low. Thus iron transfer out of the duodenalcells to the blood is increased. The reverseholds when iron stores are replete. Intestinalabsorption of iron decreases as enzyme andtransporter synthesis is decreased, and exitfrom the enterocytes decreases as the forma-tion of ferritin is increased.

Summary1. Approximately 9 L of water enters the GItract per day. Of this amount, 2 L is ingested,and 7 L is secreted into the lumen. The smallintestine absorbs approximately 8.5 L and thecolon 0.4 L, thus leaving only 100 mL to be ex-creted in the stool.2. The absorption of water occurs by diffusiondown an osmotic gradient created by the ab-sorption of Na+, Cl−, other electrolytes, andnutrients such as sugars and amino acids.3. Four mechanisms account for the absorp-tion of Na+: passive diffusion, countertrans-port with H+, cotransport with organic solutes(sugars and amino acids), and cotransportwith Cl−. The presence of these mechanismsvaries along the length of the bowel.4. Throughout the bowel, Cl− is absorbedpassively down its electrical gradient. In ad-dition to being absorbed with Na+, Cl− is ab-

sorbed in the distal ileum and colon in ex-

change for , which is secreted intothe lumen and accounts for the alkalinity ofstool water.5. Crypt cells contain channels for Cl− secre-tion in their apical membranes that respondto increases in cAMP. Various toxins, such ascholera toxin, and GI peptides, such as VIP,trigger secretion via this mechanism, whichdepends on the Na+,K+-ATPase of thebasolateral membrane.6. The small intestine actively absorbs Ca2+

by a process dependent on vitamin D, whichstimulates the synthesis of a channel proteinin the apical membrane, a cytoplasmic bind-ing protein, and Ca ATPase in the basolater-al membrane.7. Most iron is absorbed as inorganic iron.Ferric iron is reduced by the enzyme DCYTBin the brush border to ferrous iron, whichis transported into the cell by the divalentmetal transporter, DMT1. If body stores are

filled, most is bound to ferritin and lost whenthe cell is shed. During depletion, the ironexits the cell via the FPN1 transporter, is ox-idized by HEPH, and is bound to TF and car-ried in the blood. Heme is also absorbed andcan exit the cell intact or be broken down inlysosomes to release ferrous iron.

KEY WORDS ANDCONCEPTSTranscellular pathwaysParacellular pathwaysTight junctions/zonulae oc-cludensElectrogenic potentialOsmotic diarrheaSecretory diarrheaVitamin DFerritin

Suggested ReadingsBinder, H. J., Sandle, G. I. Electrolyte transport in the

mammalian colon. In Johnson L. R., ed. :Physiology of the Gastrointestinal Tract, ed 3, NewYork: Raven Press, 1994.

Chang, E. B., Rao, M. C. Intestinal water and electro-lyte transport: mechanisms of physiological andadaptive responses. In Johnson L. R., ed. :Physiology of the Gastrointestinal Tract, ed 3, NewYork: Raven Press, 1994.

Collins, J. F., Anderson, G. J., Molecular mechanismsof intestinal iron transportJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

Dharmsathaphorn, K. Intestinal water and electrolytetransport. In: Kelly W. N., ed. Textbook of InternalMedicine. Philadelphia: Lippincott, 1989.

Kiela, P. R., Collins, J. F., Ghishan, F. K., Molecularmechanisms of intestinal transport of calcium,phosphate, and magnesiumJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

Kiela, P. R., Ghishan, F. K., Na+/H+ exchange in mam-malian digestive tractJohnson, L. R., eds.

Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

Montrose, M. H., Small intestine, absorption and se-cretionJohnson, L. R., eds. Encyclopedia ofGastroenterology; vol 3. Academic Press, SanDiego, 2004:399–404.

Thiagarajah, J. R., Verkman, A. S., Water transport inthe gastrointestinal tractJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

1 3

Regulation of FoodIntake

Object ives

Understand the importance of food intaketo clinical medicine.Discuss the role of the nervous system inthe regulation of food intake.Explain the role of the endocrine system inthe regulation of metabolism and food in-take.Discuss the role of the gastrointestinal (GI)system in the regulation food intake.

Understand how input from the nervous,endocrine, and GI systems is integrated toregulate food intake and metabolism.Discuss the various treatments forobesity.

The human species evolved during a timewhen the source of the next meal was highlyuncertain. As a result, the gastrointestinal(GI) tract evolved to optimize the processingof ingested material when it became avail-able. Receptive relaxation allows the stom-ach to accommodate large volumes withminimal increases in gastric pressure. Di-gestive enzymes are secreted in great excess.The secretion of pancreatic lipase, for ex-ample, must be reduced by at least 80% be-fore steatorrhea occurs. There is significantoverlap in the specificity of transport pro-teins or carriers for the absorption of most

amino acids. Indeed, even the absorptivesurface of the small intestine can be reduced60% to 70%, as long as sufficient ileum re-mains to reabsorb bile acids and to absorbvitamin B12, before increased amounts of nu-trients appear in the stool.

The result is that virtually all ingested car-bohydrate, protein, and fat are broken downand absorbed. It is impossible to saturate thedigestive and absorptive capacities of the GItract. This situation was advantageous whenacquiring a meal was uncertain and also re-quired an expenditure of calories in the formof exercise, but now that the nearest mealis available by opening the refrigerator dooror, worse, pulling into the parking lot of thenearest convenience store or fast food res-taurant, the result is an epidemic of obesitywith its sequelae of diabetes, cardiovasculardisease, and some forms of cancer.

At present, more than two thirds of Amer-icans are overweight, and one third can beclassified as obese. The prevalence of obesity

in children has increased markedly. Obesityhas now displaced cigarette smoking as thenumber one health problem in the nation.In the United States approximately 300,000deaths per year are directly attributed toobesity. In rare cases, obesity can be causedby a gene mutation, but in an overwhelmingmajority of instances, obesity is the result ofa long-term imbalance between intake andexpenditure of calories. These two quantitiesmust remain equivalent to maintain bodyweight. Although a certain amount ofweight control can be effected by increasingcaloric expenditure in the form of exercise,the fact of the matter is that most of us over-eat.

Appetite ControlIn view of the recognized importance of nor-mal body weight for maintaining health, anunderstanding of the mechanisms regulatingfood intake seems imperative. Current know-ledge of the regulation of food intake is farfrom complete, however, and only in the pastfew years has sufficient evidence been accu-mulated for inclusion in a textbook of GIphysiology. In fact, knowledge about this as-pect of the field lags far behind that on thetopics covered in other chapters of this book.Another significant difference between thissubject and those of the other chapters is thatthe regulation of food intake depends heavilyon contributions from systems other than thedigestive system—namely, the endocrine andnervous systems.

The Nervous SystemSignals affecting food intake are integrated inthe brain. These signals include emotions andlearned behavior, as well as hormonal andneural input from the endocrine system andthe GI tract. Input provides information re-garding total energy stores and the presenceof nutrients within the digestive tract. In ad-dition, the vagus nerve relays input regardinggastric distention, secretory activity, and therelease of various hormones from the stomachand duodenum.

HypothalamusMost of the integration of signals affectingfood intake takes place in the arcuate nucleusof the hypothalamus. Two pathways exist:one inhibiting food intake and increasingmetabolism and the other stimulating food in-take and inhibiting metabolism ( Fig. 13-1).

The melanocortin pathway is made up ofappetite-inhibiting neurons containing pro-opiomelanocortin (POMC), which releasesα-melanocyte-stimulating hormone (α-MSH). α-MSH binds melanocortin receptors(MC4), present on second-order neurons, toinhibit food intake and increase the rate ofmetabolism. The stimulation of feeding isprovided by the neuropeptide Y (NPY)pathway. Hunger signals stimulate the re-lease of NPY, which binds to Y1 receptors toincrease feeding behavior and the storage ofcalories. It would make little sense for boththese pathways to be operating at the sametime, and the NPY system also releasesagouti-related peptide (AgRP), which is anantagonist of the MC4 receptor. In addition,peptides that stimulate the melanocortin sys-tem inhibit the NPY system. Some cases ofobesity in humans have been traced to muta-tions in the POMC and MC4R genes. Ap-proximately 5% of cases of childhood obesityhave been linked to MC4R mutations.

FIGURE 13-1 Integration of signals regu-lating food intake and metabolism by thecomponents of the arcuate nucleus of thehypothalamus. AgRP, agouti-related pep-tide; MC4R, melanocortin receptor; αMSH,α-melanocyte-stimulating hormone; NPY,neuropeptide Y; POMC, pro-opiomelano-cortin.

Enteric Nervous System AndVagus NerveThe enteric nervous system plays a profoundpart in the regulation of GI motility and se-cretion. Its receptors sense different chemic-

als present in foodstuffs, changes in muscletension, and various peptides released fromendocrine cells and nerves present in the gut.Approximately 75% of vagal fibers are af-ferent, and much of this information is re-layed to vagal nuclei in the brain. In somecases this input causes an efferent signal alsorelayed by vagal nerves that results in achange in gut function—a so-called vagov-agal reflex.

Most afferent vagal fibers pass through thenodose ganglion and terminate in the nucle-us tractus solitarius (NTS) of the hindbrain.The hindbrain is able to regulate food intakein response to peripheral signals if inputfrom higher centers is surgically eliminated.Several peptides that stimulate satiety anddecrease feeding are known to activate re-ceptors present on vagal afferents. In addi-tion, the vagus nerve relays signals initiatedby distention of the stomach. Vagal signalingto the NTS is integrated with information re-ceived by the hypothalamus to produce the

appropriate responses in feeding behaviorand metabolism. Experiments in which vag-al afferent activity was blocked either chem-ically or surgically demonstrated the import-ance of this pathway in the overall regula-tion of food intake. In these studies, the in-hibition of sham feeding by nutrient infusionwas prevented; the amount of material in thestomach no longer influenced meal size; andthe effects of satiety hormones were elimin-ated.

The Endocrine SystemThe endocrine system is concerned primarilywith the long-term regulation of food intakeand the maintenance of body weight.Normally, body weight is maintained withina relatively constant range over long periodsof time despite changes in physical activity,metabolic demand, and caloric intake. For ex-ample, after an illness, humans increase foodintake until lost weight is regained. Bodyweight then plateaus at or near the preillnesslevel, and food intake returns to normal. Thesame phenomenon can be observed in anim-als that have been fasted or force-fed to causeweight loss or gain, respectively. In each case,when the animal is allowed to eat ad libitum,food intake either increases or decreases tobring body weight back to normal levels.Long-term appetite and body weight are nowknown to be regulated, at least in part, by hor-mones from the pancreas and adipose tissue.

( Table 13-1 lists hormones believed to affectfood intake in humans.)

TABLE 13-1Hormones Affecting Food Intake in Hu-mans

AgRP, agouti-related peptide; CCK, cholecystokinin;NPY, neuropeptide Y; POMC, pro-opiomelanocortin;PYY, peptide YY.

InsulinInsulin is produced by the beta cells of theendocrine pancreas and regulates glucoseuptake, the storage of absorbed nutrients,and caloric or energy balance. Insulin canbe transported across the blood-brain barrierand binds to receptors present in areas ofthe hypothalamus that control food intake.In patients with type 1 diabetes mellitus, theabsence of adequate insulin is associatedwith increased food intake. In rodents, ad-ministration of insulin to the brain reducesfood intake, whereas similar administrationof insulin antibodies increases feeding beha-vior and weight gain. Additional evidenceindicates that insulin potentiates satietyfactors released from gut endocrine cells.

LeptinUntil the 1990s, fat was believed to do littlebut store calories and act as an insulator. In

1994 the discovery of leptin, an appetite-suppressing hormone secreted by fat cells,started a new era of research involving fatand the control of food intake. Leptin recept-ors have been identified on neurons presentin both pathways in the arcuate nucleus ofthe hypothalamus. The pathway producingthe appetite-stimulating peptides NPY andAgRP is inhibited by leptin, and the pathwayproducing POMC, which inhibits food in-take, is stimulated by leptin. Leptin is alsosecreted from endocrine cells in the stomachin response to feeding and cholecystokinin(CCK). This is in contrast to the leptin foundin fat cells that is released constitutively.Leptin receptors are also present on vagal af-ferent neurons. Disruption of leptin recept-ors in the hypothalamus produces onlymodest obesity compared with that of totalreceptor knockout. This finding suggeststhat the effects of leptin on vagal afferent re-ceptors are more important. Leptin has beendemonstrated to increase the satiety re-

sponse to CCK and may sensitize vagal af-ferent neurons to this gut hormone.

Thus leptin appears to be part of a neg-ative feedback system for the regulation offood intake. As fat stores increase or duringthe response to a meal, more leptin is re-leased, food intake is inhibited, and energyexpenditure is increased. The discovery ofleptin created great anticipation that it couldbe used to reduce food intake in obese per-sons, until investigators showed that mostobese persons have high circulating levelsof the hormone. Thus, although exogenousleptin reverses obesity in humans caused byits absence, leptin deficiency is not the usualreason for overeating and obesity.

The GastrointestinalSystemEndocrine cells lining the GI tract are thesource of several peptides known to regulatefeeding behavior. Some peptides act on vagalafferents, thereby relaying information to thesatiety center in the hindbrain. Others aretransported through the blood-brain barrierand act directly on the hypothalamus. The in-formation reaching these two centers is integ-rated into the overall satiety/hunger response.

CholecystokininCCK was the first peptide shown to elicit sati-ety. In 1973 Smith, Young, and Gibbs showedthat CCK injection caused rats to stop eatingand begin grooming. This response occurredin animals with an open gastric fistula, whichexcluded gastric distention as a stimulus. As

discussed in Chapter 1, CCK is released fromI cells in the duodenal mucosa in responseto fat and protein digestion products. CCKcauses its inhibition of feeding by acting onvagal afferents because its effects are re-duced by vagotomy or by chemical destruc-tion of the vagal afferents with capsaicin.The effect of CCK also is inhibited by lesionsof the NTS. CCK1 receptors are present onintestinal vagal afferents, a finding stronglysupporting the idea that the short-term reg-ulation of prandial satiety is largely the res-ult of the release of CCK. The CCK1 recept-ors on vagal afferents transmit signals to theNTS, thus decreasing the expression ofmelanin RNA and inhibiting the release ofghrelin and the expression of its receptor.One of the physiologic effects of CCK also isthe inhibition of gastric emptying. This res-ults in increased gastric distention and con-tributes to the satiety response. In humans,the infusion of CCK inhibits food intake anddecreases feeding time, and the infusion of a

CCK1 receptor antagonist produces the op-posite effects. The arcuate nucleus of the hy-pothalamus and the NTS of the hindbrainare connected by reciprocally projectingneurons. Thus the long-term effects of cent-rally acting satiety hormones are potentiatedby the short-term release of peripherally act-ing CCK.

Peptide YYPeptide YY (PYY) is another candidate fora short-term satiety factor released from thegut. Like NPY, it is a member of the pancre-atic polypeptide family and is produced asa 36–amino acid tyrosine containing peptide.PYY is released from enteroendocrine cells(L cells) of the ileum and colon by fat diges-tion products and may act to inhibit gastricemptying and secretion at the end of a meal.Circulating PYY reaches the hypothalamusvia semipermeable capillaries of the medianeminence to bind Y2 receptors, thereby in-

hibiting NPY neurons and releasing inhib-ition of POMC neurons. In humans, intra-venous infusion of PYY in amounts yield-ing blood levels similar to those following ameal reduces food intake in both lean andobese persons. Obese persons have lower en-dogenous serum levels of PYY than do thosein control subjects of normal weight. Unlikethe case for leptin, persistent administrationof PYY to obese subjects results in weightloss. Thus there is interest in PYY as a pos-sible appetite suppressor. However, theoverall significance of PYY both physiologic-ally and clinically in the control of food in-take has not been established.

GhrelinGhrelin is a 28–amino acid peptide secretedprimarily by endocrine cells in the oxynticgland area of the stomach. Gastrectomy re-duces plasma ghrelin levels by 65%, a find-ing indicating significant contributions from

extragastric sites. These include the hypo-thalamus, small and large intestines, pan-creas, and the kidney. Ghrelin binds to thegrowth hormone secretagogue receptor,stimulates the release of growth hormonefrom the pituitary, and increases the appet-ite, gastric motility, secretion of gastric acid,adipogenesis, and insulin secretion. Plasmalevels of ghrelin increase during fasting,peak just before food intake begins or whenthe subject is expecting a meal, and fall with-in an hour of the start of feeding. Neitherprotein intake nor gastric distention associ-ated with the intake of a meal inhibitsghrelin release. However, oral or intraven-ous glucose and a high-fat meal reducedplasma levels of ghrelin. In the hypothalam-us, ghrelin stimulates neurons of the arcuatenucleus that express NPY. It also exerts ac-tions directly on vagal afferents and on thedorsal vagal complex.

Plasma ghrelin levels correlate with a pa-tient’s nutritional status. Levels are high in

lean people, and intravenous ghrelin in-creases food intake in persons of normalweight. Ghrelin plasma levels are low inobese persons and increase only after weightloss, a finding suggesting that increased cir-culating levels of the hormone are not re-sponsible for overeating. Following bypasssurgery for obesity, plasma ghrelin de-creases further from already low levels, a re-sponse accompanied by decreased hunger.Patients with anorexia nervosa have highplasma levels, which return to normal afterweight gain. Additional evidence from an-imal experiments indicates that ghrelin in-hibits the release of leptin and that leptin hasa negative influence on ghrelin release. A ge-netic deletion in mice that causes a defect inthe mechanisms leading to satiety results inhyperphagia and abnormally high levels ofplasma ghrelin. Taken together, these dataindicate that ghrelin initiates the feeding re-sponse.

Additional PeptidesOther peptides from the GI tract have beenshown to inhibit food intake and may haveanorectic functions. Current research is inprogress involving glucagon-like peptide 1(GLP-1), oxyntomodulin (OXM), and pan-creatic polypeptide (PP). In addition to in-hibiting food intake, GLP-1 stimulates in-sulin release and inhibits gastric emptying.OXM, like GLP-1, is a product of the pre-proglucagon gene and has potent inhibitoryeffects on food intake in rodents. Its effects,however, are exerted on the arcuate nucleus,whereas those of GLP-1 are confined to thebrainstem. PP reduces food intake in micewhen it is administered peripherally, butcentral administration produces the oppositeeffect. In humans, PP inhibits the intake offood. Additional experiments are necessaryto elucidate whether any of these peptideshas a significant physiologic role in the regu-lation of caloric intake.

CLINICALAPPLICATIONSFigure 13-2 presents the mostlikely approximation of currentknowledge regarding the regula-tion of food intake. The agentsshown, in addition to severalothers and/or their receptors, arecandidates for the developmentof drugs to treat obesity. Leptinis effective in treating the rarecases of leptin deficiency, butresistance to the drug in the morecommon forms of obesity limitsits usefulness. Two drugs arecurrently licensed to cause lossof weight. One of these inhibitspancreatic lipase and results inmaldigestion and malabsorptionof fat. The resulting steatorrheais an unpleasant side effect, andthe effectiveness of the drug is

limited. The other acts centrallyto prevent the reuptake of sero-tonin and norepinephrine. It alsomay have adverse side effects, al-though it does reduce appetite.

FIGURE 13-2 Summary ofmechanisms involved in theregulation of food intake. CCK,cholecystokinin; NPY,neuropeptide Y; NTS, nucleustractus solitarius; POMC, pro-opiomelanocortin; PYY, pep-tide YY.

With greater frequency, obesepatients with related healthproblems are turning to surgeryas a means to lose weight.Weight reduction, or bariatric,surgery has proved to be a suc-cessful and permanent solutionfor many persons. The first pro-cedures put into general practicewere designed to decrease theabsorption of ingested food bybypassing most of the absorptivesurface of the small bowel. In themost popular of these proced-

ures, called jejunoileal bypass,the intestine was transected nearthe duodenal-jejunal border, thejejunal end was closed, and theduodenal end was anastomosedto the distal ileum. The problemscaused by malabsorption,however, made this procedureundesirable.

Currently, gastric bypass is themost commonly performed pro-cedure. A small gastric pouch iscreated to receive esophagealcontent. It in turn is connecteddirectly to the small intestine, sothat the storage function of thestomach is eliminated, thus redu-cing food intake. Weight loss of65% to 80% of excess body massis typical of most patients. Med-ically more significant is a dra-matic reduction in comorbidities.

These include a correction in hy-perlipidemia, decreased hyper-tension, improvement in ob-structive sleep apnea, and a re-duction in gastroesophageal re-flux disease in almost all pa-tients. Of major interest is a cur-rently unexplained reversal oftype 2 diabetes in up to 90% ofpatients that usually leads tonormal levels of blood glucosewithout medication, sometimeswithin days following surgery.There was an 89% reduction inmortality over 5 years followingsurgery in a large clinical trialwhen compared with a nonoper-ated group of obese subjects.

Summary1. Obesity has become the number one healthproblem in the United States.2. Our knowledge of the regulation of food in-take is incomplete but has increased rapidlysince 2000.3. Food intake is regulated by the nervous, en-docrine, and GI systems.4. Satiety and hunger signals are integratedin centers in the arcuate nucleus of the hypo-thalamus and in the nucleus tractus solitariusof the hindbrain to regulate food intake andmetabolism.5. Long-term regulation is provided by theendocrine system in the form of insulin re-leased from the pancreas and leptin releasedfrom fat cells. Both these hormones inhibit theappetite and thereby limit food intake.6. GI peptides such as PYY, CCK, and ghrelinare short-term regulators of food intake. PYYacts on the arcuate nucleus to suppress the

appetite, whereas ghrelin acts on it to in-crease food intake. CCK and gastric disten-tion activate vagal afferent fibers to the hind-brain to inhibit food intake and decrease theduration of a meal.

KEY WORDS ANDCONCEPTSArcuate nucleusMelanocortinNeuropeptide YNucleus tractus solitariusVagal afferentsInsulinLeptinCholecystokininPeptide YYGhrelin

Suggested Readings

Badman, M. K., Flier, J. S. The gut and energy bal-ance: visceral allies in the obesity wars. Science.2005; 307:1909–1914.

Blackman, S. The enormity of obesity. Scientist May.2004; 24:20–24.

Chao, C., Hellmich, M. R., Gastrointestinal peptides:gastrin, cholecystokinin, somatostatin, andghrelinJohnson, L. R., eds. Physiology of theGastrointestinal Tract, ed 5, vol 1. San Diego: El-sevier, 2012.

De Lartigue, G., Raybould, H. E., The gastrointestinaltract and control of food intakeJohnson, L. R., eds.Physiology of the Gastrointestinal Tract, ed 5, vol2. San Diego: Elsevier, 2012.

Konturek, S. J., Konturek, J. W., Pawlik, T., Brzo-zowski, T. Brain-gut axis and its role in the con-trol of food intake. J Physiol Pharmacol. 2004;55:137–154.

Rindi, G., Torsello, A., Locatelli, V., Solcia, E. Ghrelinexpression and actions: a novel peptide from anold cell type of the diffuse endocrine system. ExpBiol Med. 2004; 229:1007–1016.

Stephens, P. The endocrinology of pediatric obesity.Endocr News. October:24-27, 2004.

A

Appendix

Review ExaminationMultiple ChoiceSelect the best answer:1. If a peptide belonging to the gastrin/cholecystokinin (CCK) family and having asulfated tyrosyl residue in the seventh pos-ition from the C-terminus is desulfated, themost likely consequence for activity of thepeptide will be

a. a pattern of activity identical to that ofgastrin.

b. no change in pattern of activity.c. increased ability to stimulate gallbladder

contraction.d. decreased ability to stimulate gastric acid

secretion.e. a pattern of activity identical to that of

CCK.2. Gastrointestinal (GI) hormones

a. stimulate their target cells from the lu-minal side of the gut.

b. are for the most part inactivated as theypass through the liver.

c. are released from discrete glands withinthe mucosa of the GI tract.

d. pass through the liver and heart beforereaching their targets.

e. are bound to plasma proteins in theblood.

3. Cholecystokinina. stimulates gastric emptying.b. is released by vagal stimulation.c. is released by protein and fat in the

proximal small bowel.d. is released by distention when food

enters the small bowel.e. is an important stimulator of gastric

acid secretion.4. Which of the following is not true aboutgastrinoma (Zollinger-Ellison syndrome)?

a. Patients usually present with gastric ul-cer.

b. Patients develop diarrhea.c. Patients often have fat in their stools.d. Symptoms disappear after total gastrec-

tomy.e. Following secretin injection, the levels

of gastrin in the serum increase.5. Stimulation of an intrinsic nerve in the in-testine causes contraction of an intestinalmuscle cell through the release of whichneurotransmitter?

a. Acetylcholine (ACh)b. Nitric oxide (NO)c. Norepinephrined. Somatostatine. Vasoactive intestinal peptide (VIP)

6. A nerve ending that releases NO onto asmooth muscle cell of the jejunum is injectedwith a dye that spreads throughout thenerve. The nerve cell body labeled by the dyemost likely will be located in the

a. brain.b. celiac ganglion.c. myenteric plexus.

d. sacral region of the spinal cord.e. thoracic region of the spinal cord.

7. A muscle cell that has no striations and aratio of thin to thick filaments of 15:1 mostlikely would be found in which region of thegastrointestinal tract?

a. External anal sphincterb. Lower esophageal sphincter (LES)c. Pharynxd. Tonguee. Upper esophageal sphincter (UES)

8. In the presence of drug X, application ofACh to a bundle of gastric muscle cellscauses membrane action potentials, an in-crease followed by a decrease in intracellularfree calcium, but no contractile response.Drug X most likely is inhibiting which stepin the contraction-relaxation process?

a. Activation of myosin light chain kinaseb. Binding of ACh with membrane recept-

orsc. Opening of membrane calcium channels

d. Opening of sarcoplasmic reticulum cal-cium channels

e. Spread of excitation among muscle cells9. A lesion is made that results in loss ofprimary peristaltic contractions of thepharynx and esophagus, but secondary peri-stalsis of the lower esophagus occurs on dis-tention of the esophageal body. The lesionmost likely is in the

a. cortical region of the brain.b. cricopharyngeal muscle.c. enteric nerves.d. nucleus ambiguus of the vagus.e. pharyngeal muscle.

10. A segment of esophagus is removed andplaced in a tissue bath. The circular musclein the segment contracts tonically and re-laxes on stimulation of the nerves intrinsicto the segment. The segment is most likelyfrom which region of the esophagus?

a. Distal body of the esophagusb. LESc. Middle body of the esophagus

d. Proximal body of the esophaguse. UES

11. A catheter that monitors pressure at itstip is inserted through the nose and passedan unknown distance. Between swallows itrecords a pressure that is subatmosphericand fluctuates during the respiratory cycle,decreasing during inspiration and increasingduring expiration. In which region is thecatheter tip most likely located?

a. Esophageal body above the diaphragmb. Esophageal body below the diaphragmc. LESd. Orad region of the stomache. UES

12. A patient experiences gastric “fullness”after eating only a small quantity of food.Manometry reveals normal peristalsis inboth the upper and lower esophagus, butno receptive relaxation of the orad stomach.These findings are best explained by a defectin the

a. nucleus ambiguus of the brainstem.

b. dorsal motor nucleus of the brainstem.c. vagal nerves.d. enteric nerves.e. celiac ganglion.

13. Contractions of the orad stomach, prox-imal and distal antrum, pylorus, and prox-imal duodenum are monitored in a subjectduring the emptying of two meals that areidentical except for their fat content. Com-pared with the low-fat meal, the meal high infat would elicit

a. a decrease in the force of pyloric con-tractions.

b. an increase in the force of peristaltic an-tral contractions.

c. an increase in the number of peristalticantral contractions.

d. an increase in the number of segment-ing duodenal contractions.

e. an increase in the number of tonic con-tractions of the orad stomach.

14. Slow waves are recorded from the oradstomach, proximal and distal antrum, and

proximal duodenum in a fasted subject.Slow waves recorded during the burst phaseof the migrating motor complex (MMC),compared with slow waves recorded duringthe relaxed phase, are characterized by

a. a decrease in the apparent propagationvelocity of antral slow waves.

b. a decrease in the frequency of duodenalslow waves.

c. an increase in the amplitude of antralslow waves.

d. an increase in the frequency of antralslow waves.

e. the occurrence of slow waves in theorad stomach.

15. Compared with the gastric motility re-sponse to a meal in an individual with intactvagus nerves, the response in an individualwhose vagus nerves have been cut at a leveljust above the diaphragm would be charac-terized by

a. decreased emptying rate of liquids.b. decreased emptying rate of solids.

c. increased accommodation of the meal.d. increased mechanical reduction of food

particle size.e. increased mixing of contents.

16. The rate of gastric emptying of a mixedmeal of solid foods and liquids would be de-creased by

a. blocking activation of receptors in theduodenal mucosa.

b. enhanced tonic contraction of the oradstomach.

c. infusing an isotonic solution of sodiumchloride into the duodenum.

d. infusing an isotonic solution of sodiumchloride into the stomach.

e. infusing an isotonic solution of sodiumoleate into the duodenum.

17. A patient experiences a rapid rate oftransit of contents from the duodenum to thececum. What characteristic would contrac-tions recorded at various loci of the small in-testine exhibit during this time?

a. Frequency greater than that of the slowwave

b. Low in forcec. Mostly peristalticd. Mostly segmentinge. Mostly tonic

18. Intravenous injection of a hormone ini-tiates a phase of intense sequential contrac-tions of the proximal duodenum that ap-pears to migrate slowly toward the cecum.Which hormone was most likely injected?

a. CCKb. Gastrinc. Motilind. Secretine. VIP

19. A region of the intestine contracts weaklyon stimulation of its extrinsic nerves. Disten-tion of the region elicits a peristaltic reflex,but with weak contractions. Slow waveactivity is absent. Taken together, these find-ings suggest a disorder of the

a. enteric nerves.

b. parasympathetic nerves.c. release of motilin.d. smooth muscle cells.e. sympathetic nerves.

20. A normal subject’s small intestinal con-tractions are recorded from three loci spaced5 cm apart. Over a period of 2 hours, con-tractions occur at each site seemingly at ran-dom, with the interval between any two con-tractions being 5 seconds or a multiple of 5seconds. Only rarely do contractions at thethree loci seem to be in sequence. These dataindicate that

a. contractions are being recorded fromthe ileum.

b. the subject is in a fasted state.c. every slow wave is being accompanied

by a contraction.d. the contractions are causing rapid abor-

al transit of contents.e. the contractions are mostly of the seg-

menting type.

21. Intraluminal pressure is monitored froma region of the colon that exhibits a relativelyconstant resting pressure of about 20 mmHg. When an adjacent region of the colonis distended, resting pressure falls to near0 and then increases slowly back toward 20mm Hg even though the distention persists.The region being monitored is most likelythe

a. ascending colon.b. external anal sphincter.c. ileocecal sphincter.d. internal anal sphincter.e. transverse colon.

22. Segmental contractions of the colona. increase in frequency in response to in-

creased circulating levels of epineph-rine.

b. occur more often than do peristaltic con-tractions of the colon.

c. occur at a higher frequency in the sig-moid colon than in the rectum.

d. occur at a frequency that is higher thanthat for slow waves in the same region.

e. are accompanied by the loss of haustralmarkings.

23. Relaxation of the ileocecal sphincter willoccur during each of the following except

a. eating a meal.b. distention of the ileum.c. distention of the colon.d. injection of gastrin.e. injection of CCK.

24. In a patient in whom resting tone of theinternal anal sphincter is normal, distentionof the rectum induces normal relaxation ofthe internal anal sphincter, no change in toneof the external anal sphincter, and no sensa-tion of the urge to defecate. These findingsare consistent with the finding of damage tothe

a. enteric nerves.b. internal anal sphincter.c. vagus nerve.d. spinal cord.

e. transverse colon.25. The digestive action of saliva on starchresults from

a. lactoferrin.b. lingual lipase.c. ptyalin.d. kallikrein.e. bradykinin.

26. At high rates of secretion, compared withlow rates, saliva would have a lower concen-tration of

a. Na+.b. water.c. Cl−.

d.27. All of the following are characteristic ofsaliva except that

a. it has a high K+ concentration.b. there is a large volume of secretion rel-

ative to the weight of the glands.c. both parasympathetic and sympathetic

stimulation increase its flow.

d. it is hypotonic.e. it is primarily regulated by hormones.

28. Salivary secretion is inhibited bya. smell.b. taste.c. nausea.d. pressure of food in the mouth.e. sleep.

29. Which of the following substances orcombinations will produce the highest rateof acid secretion? (Each compound is givenat its half maximal dose.)

a. Histamineb. Gastrinc. Gastrin plus secretind. AChe. Histamine plus gastrin

30. Acid secretion during the cephalic re-sponse to a meal

a. fails to occur when the antrum is acidi-fied.

b. is triggered by the entrance of food intothe stomach.

c. is prevented by vagotomy.d. is inhibited by insulin injection.e. is stimulated only by ACh acting on the

parietal cells.31. Following the administration of histam-ine to a fasting individual, all of the follow-ing will occur within the parietal cells except

a. a decreased number of tubulovesicles.b. increased carbonic anhydrase activity.c. increased H+,K+-adenosine triphos-

phatase (ATPase) activity.d. an increased number of mitochondria.e. an increased area devoted to the intra-

cellular canaliculus.32. According to the two-component hypo-thesis for gastric acid secretion, the H+ con-centration in gastric secretion increases withthe rate of secretion because

a. the volume of the oxyntic componentincreases.

b. the concentration of H+ being secretedby the parietal cells increases.

c. the volume of the nonoxyntic compon-ent decreases.

d. the secretion of Na+ is inhibited.e. the secretion becomes hypertonic.

33. Antral gastrin release is stimulated by allof the following except

a. bombesin gastrin-releasing peptide(GRP).

b. ACh.c. fat in the stomach.d. protein digestion products in the stom-

ach.e. distention of the antrum.

34. The presence of acid (pH <3) in the duo-denum

a. inhibits gastrin release via somatostatin.b. increases pancreatic bicarbonate secre-

tion.c. decreases bile production.d. increases gastric acid secretion.e. inhibits pancreatic enzyme secretion.

35. In someone with a total absence of gastricparietal cells, one would expect to find eachof the following except

a. decreased digestion of dietary protein.b. decreased absorption of vitamin B12.c. little or no pepsin activity.d. increased growth of gut bacteria.e. lower than normal pancreatic bicarbon-

ate secretion.36. Administration of a drug that blocks theH+,K+-ATPase of the parietal cells of a secret-ing stomach

a. will have no effect on the volume of se-cretion.

b. will increase the concentration of H+ inthe secretion.

c. will decrease the concentration of Na+ inthe secretion.

d. will decrease the pH of the gastric ven-ous blood.

e. will decrease the potential differenceacross the stomach.

37. The interruption of vagal afferent fibersfrom the stomach would

a. decrease the acid secretory response tosham feeding.

b. decrease the release of gastrin by diges-ted protein.

c. decrease acid secretion in response todistention.

d. decrease the release of somatostatin.e. increase acid secretion in response to

histamine.38. Between meals, when the stomach isempty of food,

a. it contains a large volume of juice withpH approximately equal to 5.

b. gastrin release is inhibited by a stronglyacidic solution.

c. it contains a small volume of gastricjuice with a pH near neutral.

d. bombesin acts on the parietal cells to in-hibit secretion.

e. it secretes large volumes of weakly acid-ic juice.

39. During the cephalic phasea. secretin stimulates pepsin secretion.b. CCK stimulates pancreatic enzyme se-

cretion.c. ACh stimulates the G cell to release

gastrin.d. bombesin stimulates parietal cell secre-

tion.e. ACh stimulates pancreatic enzyme se-

cretion.40. In humans, maximal rates of pancreaticbicarbonate secretion in response to a mealresult from

a. the effects of small amounts of secretinbeing potentiated by ACh and CCK.

b. large amounts of secretin released fromthe duodenal mucosa.

c. VIP acting on the ductule cells.d. potentiation between CCK and ACh re-

leased from vagovagal reflexes.e. potentiation between small amounts of

secretin and gastrin.41. Vagal stimulation

a. potentiates the effect of CCK on pancre-atic acinar cells.

b. directly stimulates pancreatic enzymesecretion.

c. releases CCK from the duodenal mu-cosa.

d. inhibits the effect of secretin on pancre-atic ductule cells.

e. releases secretin from duodenal mu-cosa.

42. Pancreatic enzyme secretiona. contains enzymes for the digestion of fat

and protein but not carbohydrate.b. is primarily stimulated by secretin.c. is stimulated by pancreatic polypeptide.d. originates from the ductule cells.e. occurs primarily during the intestinal

phase of the secretory response.43. Pancreatic bicarbonate

a. is secreted primarily from acinar cells.b. is secreted in quantities approximately

equal to those of gastric acid.

c. is stimulated primarily during the gast-ric phase of digestion.

d. secretion causes an increase in the pH ofpancreatic venous blood.

e. ion concentrations in pancreatic juicedecrease with increasing rates ofvolume secretion.

44. Pancreatic enzymesa. are synthesized in response to a secret-

ory stimulus.b. are stored in Golgi vesicles.c. are secreted in response to carbohydrate

in the duodenum.d. are secreted in response to sham feed-

ing.e. are involved in the breakdown of disac-

charides.45. A sample of bile taken from the gallblad-der is compared with a sample of bile col-lected as it is being secreted from the liver.Compared with hepatic bile, the gallbladderbile will differ in that its

a. bile salt concentration will be less.

b. cholesterol–bile salt ratio will be great-er.

c. osmolality will be greater.d. phospholipid concentration will be less.e. potassium concentration will be greater.

46. Bile acid A has a greater solubility in in-testinal fluid than does bile acid B. Com-pared with bile acid B, bile acid A is morelikely to be

a. a secondary bile acid.b. a trihydroxy rather than a dihydroxy

bile acid.c. absorbed passively in the jejunum.d. unconjugated.e. undissociated.

47. When the distal ileum is removed, therewill be an increase in bile acid

a. levels in hepatic venous blood.b. levels in portal venous blood.c. secretion by hepatocytes.d. storage in the gallbladder.e. synthesis by hepatocytes.

48. As the bile secreted by the hepatocytesflows through the hepatic ducts on the wayto the gallbladder, there is an increase in bile

a. bicarbonate concentration.b. bilirubin content.c. chloride concentration.d. H+ concentration.e. osmolality.

49. The rate of absorption of free galactosein the small intestine, initially occurring at asubmaximal rate, would be

a. increased by adding an equal amount ofglucose to the lumen.

b. decreased by adding amino acids to thelumen.

c. decreased by adding fructose to the lu-men.

d. increased by the addition of trehalose tothe lumen.

e. decreased by hypoxia in the enterocytes.50. Which of the following enzymes is loc-ated in the brush border and plays a role inprotein digestion?

a. α-Dextrinaseb. Carboxypeptidase Ac. Pepsind. Enterokinasee. Lactase

51. Colipase facilitates fat assimilation bya. digesting triglycerides.b. transporting fatty acids across cell mem-

branes.c. preventing the inactivation of lipase by

bile salts.d. converting prolipase to lipase.e. binding fatty acids and monoglycerides

after they have been absorbed by the en-terocytes.

52. Most medium-chain fatty acids do notappear in chylomicrons because

a. they are not absorbed by enterocytes.b. they are transported by fatty

acid–binding proteins.c. they do not bind to apoproteins.d. triglycerides containing them are not

digested by pancreatic lipase.

e. they are absorbed directly into theblood.

53. In the absence of enterokinase, onewould also expect a decrease in the activityof

a. pepsin.b. lipase.c. chymotrypsin.d. amylase.e. sucrase.

54. Amino acidsa. are primarily absorbed in the distal gut.b. are, for the most part, absorbed by pass-

ive mechanisms.c. compete with glucose for Na+ during

their absorption.d. appear in the blood more rapidly when

presented to the gut as small peptidesrather than as free amino acids.

e. are produced in the lumen primarily bythe action of endopeptidases.

55. Each of the following acts as a goodemulsifying agent except

a. cholesterol.b. bile salts.c. fatty acids.d. lecithin.e. dietary protein.

56. Colipasea. digests the ester link in

2-monoglycerides.b. is a brush border enzyme.c. has no enzymatic activity.d. lowers the pH optimum of pancreatic

lipase to match that of duodenal con-tents.

e. displaces pancreatic lipase from the sur-face of emulsion droplets.

57. The reason that patients with a congenit-al absence of one of the amino acid carriersdo not become deficient in that amino acid isthat

a. the amino acid is absorbed by passivediffusion.

b. the amino acid can make use of othercarriers.

c. the amino acid is absorbed by facilitateddiffusion.

d. peptides containing the amino acid areabsorbed by different carriers.

e. the amino acid is an essential aminoacid.

58. Within the enterocytesa. triglycerides are resynthesized in the

smooth endoplasmic reticulum.b. chylomicrons are synthesized in the

smooth endoplasmic reticulum.c. fatty acid–binding protein transports

long-chain fatty acids to the Golgi ap-paratus.

d. triglycerides are synthesized from me-dium- and short-chain fatty acids.

e. the major triglyceride resynthesis path-way makes use of dietary glycerol.

59. Of the 8 to 10 L of H2O entering the di-gestive tract per day,

a. only 100 to 200 mL is excreted in thestool.

b. most comes from the diet (includes li-quids).

c. most is absorbed in the large intestine.d. gastric secretions contribute twice the

volume of those from the pancreas.e. most is absorbed against its own con-

centration gradient.60. In the small intestine, Na+ is absorbed byeach of the following processes except

a. diffusion.b. coupled to amino acid absorption.c. coupled to galactose absorption.d. coupled to the transport of H+ in the op-

posite direction.

e. coupled to the absorption of .61. In the distal portion of the ileum,

a. most fatty acids are absorbed.

b. Cl− is absorbed in exchange for.

c. Na+ absorption occurs primarilycoupled to glucose and amino acids.

d. intrinsic factor is secreted.

e. K+ is absorbed in exchange for Na+.62. In the small intestine each of the follow-ing is true regarding Cl− absorption exceptthat

a. it occurs down its electrical gradient.b. it occurs in exchange for Na+.

c. it occurs in exchange for .d. it will result in the absorption of water.e. it occurs along the entire length of the

small bowel.63. Osmotic diarrhea may be the result ofeach of the following except

a. cholera.b. lactase deficiency.c. inactivation of pancreatic lipase.d. Zollinger-Ellison syndrome (gast-

rinoma).e. loss of mucosal surface area in the small

intestine.64. Secretion of Cl− by the small intestine

a. occurs in exchange for .b. takes place primarily in the villous cells.

c. is inhibited by ouabain.d. produces an osmotic diarrhea.e. depends on an ATPase in the brush bor-

der membrane.

Matchinga. Gastrinb. CCKc. Somatostatind. Secretine. VIPf. Histamine

65. Inhibits gastrin release when antrum isacidified66. Inhibits parietal cell secretion of acidwhen antrum is acidified67. Stimulates growth of gastric mucosa68. Released by gastrin and acts as a parac-rine to stimulate acid secretion69. Stimulates gallbladder contraction in re-sponse to fat in the duodenum

70. Stimulates intestinal secretion and re-laxes smooth muscle

Answers

Index

Page numbers followed by f indicate figures; t, tables;b, boxes.

A

Absorption, 108–127

adaptation of, 110–111

anatomy—functional associations in, 108–109

carbohydrate assimilation for, 111–115, 111f–112f

abnormalities in, 114–115, 114f

principal dietary forms of, 111

description and overview of, 109–110

electrolytes, 128–138

Ca2+, 135–136, 135f, 138

clinical applications with, 134b

intestinal secretion, 133–135, 133f

iron, 136, 137f, 138

NaCl, 130–131, 130f, 132f

transport routes for, 129–131, 130f

fluids, 128–138

bidirectional fluid flux with, 128–129, 129f

clinical applications with, 134b

iconic content of luminal fluid in, 129

intestinal secretion, 133–135, 133f

transport routes for, 129–131

fructose, 114f

glucose, 113f

intracellular events with, 122–124, 122f

monoglyceride acylation pathway, 122–123

phosphatidic acid pathway, 123–124

lipid assimilation for, 121–122, 121f

abnormalities in, 124–125

mucosal membrane's role in, 109–110, 110f

NaCl, 130–131, 130f, 132f

pancreatitis development with, 116

protein assimilation for, 113f, 116–118, 117f–118f,117t

abnormalities in, 118–119, 119f

regulation of, 113–114

transport processes for, 110

triglyceride, 122f

vitamins, 125–126, 125t

abnormality in, 126

Acetylcholine (ACh), 1, 12b, 14–15, 20

exam question on, 146, 150

histamine in relation to, 70, 70f

large intestine with, 48

pancreatic secretion with, 90f, 92

pepsin secretion stimulated by, 76

Achalasia, 27b–28b

Acid See also Amino acids Gastric secretion

bile, 94–95

chemistry of, 95–96, 96f

bile secretion, 95f, 98–100, 99f

chenodeoxycholic, 95, 96f

cholic, 95, 96f

deoxycholic, 95, 96f

folic, 125–126, 125t

histamine's role in stimulating, 69–70, 70f

lithocholic, 95, 96f

pantothenic, 125t

phosphatidic acid pathway, 123–124

secretion of, 67–68, 67f, 81

vitamin C, 125, 125t

Acinar cells

pancreatic secretion of enzymes with, 85–86, 86f,92

pancreatic secretion with, 82

Acinus

pancreatic secretion with, 82

salivary gland secretion by, 55, 56f

Action potentials, 18

Active transport, 110

Adenosine triphosphate (ATP)

large intestine with, 48

smooth muscle contractions with, 17, 18f

Amine precursor uptake decarboxylation (APUD)cells, 5

Amino acids, absorption rates of, 117f, 117t

Aminooligopeptidase, 109f

α-Amylase, 54–55, 109f

Amylopectin, 111

Anal canal, 47

motility of, 50, 50f

ANS See Autonomic nervous system

Antihistamines, 70

Antral gastrin release, exam question on, 150

Antrum, 65, 65f

mechanisms for inhibiting acid secretion in, 75f

Apolipoprotein, 123–124

Appetite control, 139–140

APUD See Amine precursor uptake decarboxylationcells

Aqueous component, pancreatic secretion with,82–83

Arcuate nucleus, 140, 140f, 144

Arginine, absorption rates of, 119f

Ascending colon, 47, 48f

contractions of, 48–49, 48f–49f

Ascorbic acid See Vitamin C

ATP See Adenosine triphosphate

ATPase, 67–68

Auerbach plexus, 39

Autonomic nervous system (ANS)

anatomy of, 13–15, 20

large intestine innervated by, 47–48

neurocrines in, 14–15

salivary gland components of, 56, 57f

B

Bacterial infections, bile ducts and gallbladder,104b–105b

Bacterial overgrowth syndrome, 124

Bicarbonate

absorption of into colon of, 132f

biliary system with, 95f

pancreatic secretion of, 83, 84f–85f

Bidirectional fluid flux, 128–129, 129f

Bile

acids, 94–95

chemistry of, 95–96, 96f

exam question on, 151

secretion of, 95f, 98–100, 99f

concentration of, 102–106, 104t

constituents of, 95–98, 96f–97f

expulsion of, 102–106

CCK with, 103–104

hepatocytes producing, 94–95, 98–100, 98f, 102f,106

inorganic ions in, 98

organic compounds in

cholesterol, 97, 97f, 100

phospholipids, 96–97, 100

pigments, 97–98, 100, 101f

salts, 95–96, 96f

Bile acid dependent, 94–95

Bile acid–dependent secretion, 100–101

Bile acid–independent secretion, 94–95, 101

Bile duct, 101–102

Bile salt excretory pump (Bsep), 100

Bile salts, 102, 104t

Bile secretion, 98–101

acids, 95f, 98–100, 99f

bilirubin in, 100, 101f

cholesterol in, 100

clinical applications with, 104b–105b

clinical tests for, 105b–106b

electrolytes in, 100–101, 102f

enterohepatic circulation in, 95f, 98–100, 99f

functional histology of liver with, 98, 98f

phospholipids in, 100

systems overview for, 94–95, 95f

water in, 100–101, 102f

Bilirubin

bile secretion with, 100, 101f

liver and gallbladder bile concentration of, 102,104t

Binding glycoprotein for immunoglobulin A (IgA),54

Biotin, 125t

Bombesin, 71 See also Gastrin-releasing peptide

Bombesin gastrin-releasing peptide (GRP)

exam question on, 150

Bottom tracing, 33f

Bradykinin, 60–61

exam question on, 149

Brush border, 108

Bsep See Bile salt excretory pump

C

Calcium (Ca2+)

absorption of, 135–136, 135f, 138

liver and gallbladder bile concentration of, 102,104t

smooth muscle contractions with, 17–18, 18f, 20

Carbon dioxide (CO2)

biliary system with, 95f

pancreatic secretion of, 83, 84f

Carbonic anhydrase, 67

Carboxyl ester lipase, 120

Carboxypeptidase, 109f

Caudad portion, 26, 27f

Caudad region contractions, 31–33, 33f

gastric peristaltic contractions with, 32f

intraluminal pressures with, 31f

peristaltic contraction with, 31, 31f

retropulsion in, 31–32

slow waves in, 32–33, 33f, 38

spike bursts in, 32

spike potentials in, 32

Cavital digestion, 109

CCK See Cholecystokinin

Cecum, 47

contractions of, 48–49, 48f–49f

Centroacinar cells, pancreatic secretion with, 82

Cephalic phase

exam question on, 150

pancreatic secretion in, 86, 87f, 92

stomach acid secretion in, 71, 71f, 81

CFTR See Cystic fibrosis transmembrane conduct-ance regulator

Chenodeoxycholic acid, 95, 96f

Chewing

major functions of, 21

reflex, 21

Chief cells, 65, 65f

Chloride (Cl−)

absorption of into colon of, 132f

biliary system with, 95f

liver and gallbladder bile concentration of, 102,104t

pancreatic secretion of, 83, 84f–85f

Cholecystokinin (CCK), 2, 12b

actions of, 7–8, 7t

bile expulsion with, 103–104

chemistry of, 3–4, 3f

discovery of, 2–3

distributions of, 5, 5f

exam question on, 146

food intake affected by, 141–142, 141t

gastric acid secretion inhibition with, 74–75, 75f

large intestine affected by, 51

pancreatic secretion with, 87–89, 90f

releasers of, 5, 6t

small intestine affected by, 44, 46

small intestine innervation with, 39–40

Cholesterol, 97, 97f

bile secretion of, 100

liver and gallbladder bile concentration of, 102,104t

Cholesterol esterase, 121

Cholesterol esterase—nonspecific lipase, 109f

Cholic acid, 95, 96f

Chronic pancreatitis, 91b–92b

Chylomicrons, 123–124

Chymotrypsin, 109f

Chymotrypsinogen, 115–116, 116f

Cimetidine, histamine-stimulated acid secretion in-hibited by, 70

Circular layer, 30

Cl− See Chloride

CO2 See Carbon dioxide

Colipase, 120

exam question on, 151–152

Constipation, 51b–52b

Contact/membrane digestion, 109

Contraction

esophageal peristalsis, 23–26, 23f–24f, 26f, 28

LES, 26, 28

peristaltic, pharyngeal muscles, 21, 22f, 28

smooth muscle in, 17–20

biochemistry of, 17–18, 18f

phasic compared to tonic, 17

Contractions

ascending colon, 48–49, 48f–49f

caudad region, 31–33, 31f–33f

cecum, 48–49, 48f–49f

descending colon, 49–50, 49f

duodenal, 36

exam question on, 149

orad region, 31

sigmoid colon, 49–50, 49f

small intestine

patterns with, 41–44, 42f–43f

types of, 40–41, 40f–41f, 46

Critical micellar concentration, 96, 121

Cystic fibrosis, 91b–92b

Cystic fibrosis transmembrane conductance regulat-or (CFTR), 134

D

Defecation, 50

Deoxycholic acid, 95, 96f

Descending colon, 47, 48f

contractions of, 49–50, 49f

Dextrins, digestion summary for, 112f

Diarrhea, 134b

osmotic, 133, 134b, 153

secretory, 134b

Diffuse esophageal spasm, 27b–28b

Digestion, 108–127

adaptation of, 110–111

anatomy—functional associations in, 108–109

carbohydrate assimilation for, 111–115, 111f–112f

abnormalities in, 114–115, 114f

principal dietary forms of, 111

cavital, 109

contact, 109

defined, 109

description and overview of, 109

enzymes important in, 109, 109f

intracellular events with, 122–124, 122f

monoglyceride acylation pathway, 122–123

phosphatidic acid pathway, 123–124

lipid assimilation for, 119–125, 121f

abnormalities in, 124–125

cholesterol esterase, 121

gastric lipase, 120

pancreatic lipase, 120, 121f

luminal, 109

membrane, 109

pancreatitis development with, 116

protein assimilation for, 115–116, 115t, 116f, 118f

abnormalities in, 118–119, 119f

salivary glands' role in, 54, 63

triglyceride, 122f, 124

vitamins, 125–126, 125t

Dipeptidase, 109f

Disaccharidase deficiency, 133

Disaccharidases, 109f

Divalent metal transporter 1 (DMT1), 136

Diverticula, 51b–52b

DMT1 See Divalent metal transporter 1

Ductular secretion, 94–95

Ductule cells, pancreatic secretion with, 82

“Dumping syndrome, ”, 37b

Duodenal contractions, 36

Duodenal ulcers, 78b–80b, 78t

Duodenum

intestinal receptors located in, 36

intraluminal pressure changes from, 40f

mechanisms for inhibiting acid secretion in, 75f

proximal, 31

E

ECL See Enterochromaffin-like cells

Elastase, 109f

Electrogenic potential, 131

Electrolytes

absorption of, 128–138

Ca2+, 135–136, 135f, 138

clinical applications with, 134b

intestinal secretion, 133–135, 133f

iron, 136, 137f, 138

NaCl, 130–131, 130f, 132f

transport routes for, 129–131, 130f

bile secretion of, 100–101, 102f

pancreatic secretion, mechanisms for, 83–84,84f–85f

saliva containing, 58, 58f

stomach secretion containing, 68–69, 69f, 80

Emesis See Vomiting

Emulsification, 119–120

Endocrine system, food intake affected by, 141–142,144

CCK, 141–142, 141t

insulin, 141, 141t

leptin, 141–142, 141t

Endocrines/hormones, 12b See also Peptides

actions of, 6–8, 7t

“candidate, ”, 2, 8–9, 8t

chemistry of, 3–5, 3f–4f

discovery of, 2–3

distribution and release of, 5–6, 5f, 6t, 14–15

exam question on, 146

gastric acid secretion inhibition with, 74

gastrointestinal, 1–12

large intestine affected by, 51

pancreatic secretion with, 87–89, 88f, 90f

regulatory role of, 1

small intestine affected by, 44, 46

Endopeptidases, 115, 115t

Enkephalins, 9–10, 9t

small intestine innervation with, 39–40

Enteric nervous system, 14, 15f, 20

food intake affected by, 140–141

Enterochromaffin-like cells (ECL), 7

histamine found in, 70, 70f

Enterocytes, 108

exam question on, 152

Enterogastrones, 3, 12b

gastric acid secretion inhibition with, 74

Enteroglucagons, 4, 8t, 9, 12b

Enterohepatic circulation, 95f, 98–100, 99f, 124

Enterokinase, 109f, 115–116, 116f

exam question on, 152

Enzymatic/protein component, pancreatic secretionwith, 82

Enzymes

pancreatic secretion of, 84–86, 86f, 92

exam question on, 151

saliva containing, 54–55

Esophagus

action of, 23

anatomy of, 23–24

efferent innervation of, 25, 26f

location of, 23

peristalsis in, 23–26, 28

control of, 23f, 25

manometric recordings from, 24f

Exopeptidases, 115, 115t

External anal sphincter, 47

exam question on, 147

Extrinsic nervous system, 13

branches of, 14f

distribution of, 20

integration of, 15f

F

Facilitated diffusion, 110

Fasciae, 16–17

Fatty acid–binding proteins, 123

Ferritin, 136, 137f, 138

Fluids

absorption of, 128–138

bidirectional fluid flux with, 128–129, 129f

clinical applications with, 134b

ionic content of luminal fluid in, 129

intestinal secretion, 133–135, 133f

transport routes for, 129–131

water absorption or secretion, 131–133, 133f

Folic acid, 125–126, 125t

Food intake

appetite control with, 139–140

clinical applications with, 143b–144b

endocrine system affecting, 141–142, 144

CCK, 141–142, 141t

insulin, 141, 141t

leptin, 141–142, 141t

gastrointestinal system affecting, 142–145

CCK, 142

ghrelin, 142–143

OXM, 143–144

peptide YY (PYY), 142

nervous system affecting, 140–141, 144

enteric nervous system, 140–141

hypothalamus, 140, 140f

vagus nerve, 140–141

regulation of, 139–145

Fructose, absorption rates of, 114f

G

Gallbladder, 94–107

bacterial infections, 104b–105b

bile expulsion from, 102–106

CCK with, 103–104

clinical applications with, 104b–105b

clinical tests for, 105b–106b

concentration of bile in, 102–106, 104t

exam question on, 151

filling, 101–102, 103f

function of, 101–102

obstruction, 104b–105b

systems overview for, 94–95, 95f

Gallstones, 105b–106b

Gastric emptying, 30–38

anatomic considerations with, 30–31

caudad region contractions with, 31–33, 31f–33f

clinical applications with, 37b

clinical tests for, 37b

exam question on, 148

gastroduodenal junction contractions with, 33, 34f

gastroduodenal junction in, 30–31, 31f

ICCs in, 31

innervation in, 30

muscle contractions with, 30, 33f

orad region contractions with, 31

proximal duodenum contractions with, 34

proximal duodenum in, 31

pylorus in, 30–31

regulation of, 35, 34–38, 35f

retropulsion in, 31–32

slow waves in, 32–33, 33f, 38

spike bursts in, 32

spike potentials in, 32

Gastric inhibitory peptide (GIP), 2, 12b

actions of, 7t, 8

chemistry of, 4, 4f

distributions of, 5, 5f

gastric acid secretion inhibition with, 74–75

releasers of, 6t

Gastric lipase, 109f, 120

Gastric mucosa

divisions of, 65, 65f

pits and glands of, 65, 65f

transport processes in, 67f

Gastric mucosal barrier, 64

Gastric phase

pancreatic secretion in, 87

stomach acid secretion in, 71–73, 72f, 81

Gastric secretion, 64–81

acid in, 67–68, 67f, 81

anatomy related to, 65–67, 65f–66f

clinical applications with, 78b–80b, 78t

constituents of, 64

electrical potential difference, origin with, 68

electrolytes in, 68–69, 69f, 80

growth of GI mucosa with, 77–80

history regarding, 64

inhibition of, 74–75, 75f

intrinsic factor with, 64, 77, 81

mucus in, 77

pepsin in, 75–76, 76f, 81

stimulants of acid in, 69–70, 80

histamine's role in, 69–70, 70f

stimulation of, 70–73

cephalic phase, 71, 71f, 81

gastric phase, 71–73, 72f, 81

gastrin release in, 73, 73f, 81

intestinal phase, 73, 74f

Gastric ulcers, 78b–80b, 78t

Gastrin, 2, 12b

actions of, 7, 7t

chemistry of, 3–4, 3f

clinical tests for, 11b–12b

discovery of, 2

distributions of, 5, 5f

exam question on, 146

histamine in relation to, 70, 70f

large intestine affected by, 51

mucosa growth regulated by, 77

pepsin secretion stimulated by, 76

releasers of, 5, 6t

small intestine affected by, 44, 46

stomach acid secretion with release of, 73, 73f

Gastrin II, 12b

Gastrinoma, 11b–12b

Gastrin-releasing peptide (GRP), 9t, 10, 71

Gastroduodenal junction, 30–31

gastric emptying, contractions in, 33, 34f

gastric emptying with, 31f

Gastroenterostomy, 37b

Gastroesophageal reflux disease (GERD), 27b–28b

Gastroileal reflex, 51

Gastrointestinal system

food intake affected by, 142–145

CCK, 142

ghrelin, 142–143

OXM, 143–144

peptide YY (PYY), 142

Gastrointestinal tract

general characteristics of, 1–2

muscles in regulation of, 13–20

nerves in regulation of, 13–20

peptides affecting, 1–12

regulation of, 1–20

GERD See Gastroesophageal reflux disease

G-Gly, 12b

Ghrelin, 2

food intake affected by, 142–143

GIP See Gastric inhibitory peptide

Glottis, 21, 22f

Glucagon, 12b

Glucose, absorption rates of, 113f

Glycine, absorption rates of, 117f, 117t

Glycocalyx, 109–110

Goblet cells, 108

GRP See Bombesin gastrin-releasing peptideGastrin-releasing peptide

H

H+ See Hydrogen ion

H2O See Water

Hartnup’s disease, 118–119

Haustra/haustrations, 47, 48f

HCO3− See Bicarbonate

Heartburn, 27b–28b

Heme, 136

Hemoglobin, 100, 101f

Hepatocytes, bile with, 94–95, 98–100, 98f, 102f, 106

HEPH See Iron oxidase hephaestin

Hiatal hernia, 27b–28b

Hirschsprung’s disease, 51b–52b

Histamine, 10

acid secretion stimulated by, 69–70

blocking of, 70

discovery of, 69

gastrin and ACh in relation to, 70, 70f

potentiation with, 69–70

Hormones, 12b See also Peptides

actions of, 6–8, 7t

“candidate, ”, 2, 8–9, 8t

chemistry of, 3–5, 3f–4f

discovery of, 2–3

distribution and release of, 5–6, 5f, 6t, 14–15

exam question on, 146

gastric acid secretion inhibition with, 74

gastrointestinal, 1–12

large intestine affected by, 51

pancreatic secretion with, 87–89, 88f, 90f

regulatory role of, 1

small intestine affected by, 44, 46

Hydrogen ion (H+)

absorption of into colon of, 132f

biliary system with, 95f

gastric juice with, 64, 67–68

pancreatic secretion of, 83, 84f

Hypothalamus, food intake affected by, 140, 140f

I

ICC See Interstitial cells of Cajal

Idiopathic pseudo-obstruction, 45b

IgA See Binding glycoprotein for immunoglobulinA

Ileocecal junction, 48

Ileocecal sphincter, intraluminal pressures with, 48f

Inorganic ions, 98

Insulin, food intake affected by, 141, 141t

Intercalated duct, 55, 56f

Internal anal sphincter, 47

Interstitial cells of Cajal (ICC)

pacemaker slow wave with, 18, 19f

small intestine motility with, 39

stomach, 31

Intestinal malabsorption, 118–119

Intestinal phase

pancreatic secretion in, 87–89, 88f, 90f, 92

stomach acid secretion in, 73, 74f

Intestinal receptors, duodenum with, 36

Intestinal secretion, 133–135, 133f

Intestine, large

anatomy of, 47–48, 53

ANS innervation of, 47–48

chemical interactions within, 48

divisions of, 47

motility of, 47–53

cecum and ascending colon contractions with,48–49, 48f–49f

clinical applications with, 51b–52b

clinical tests for, 52b

control of, 50–53, 50f

descending and sigmoid colon contractionswith, 49–50, 49f

rectum and anal canal with, 50, 50f

slow waves, 51, 53

Intestine, law of, 40–41

Intestine, small See also Duodenum

anatomy of, 39–40

contraction patterns with, 41–44, 42f–43f

MMC, 41–42, 42f–43f

slow wave activity, 42, 43f

spike potential activity, 42–43, 43f

contraction types with, 40–41, 40f–41f, 46

motility of, 39–46

clinical applications with, 45b

clinical tests for, 46b

function of contractions in, 39

ICCs in, 39

innervation in, 39–40

smooth muscle in, 39

Intestino-intestinal reflex, 44

Intracellular canaliculus, 67

Intraluminal pressure, exam question on, 148–149

Intrinsic factor, gastric juice with, 64, 77, 81

Intrinsic nervous system See Enteric nervous system

Iron, absorption of, 136, 137f, 138

Iron oxidase hephaestin (HEPH), 136

Irritable bowel syndrome, 51b–52b

Islets of Langerhans, pancreatic secretion with, 82

Isomaltase, 109f

J

Jaundice, 100

clinical applications with, 104b–105b

Jejunum, mechanisms for inhibiting acid secretionin, 75f

K

K+ See Potassium

Kallikrein, 60–61

exam question on, 149

Kwashiorkor, 91b–92b

L

Lactase, 109f

Lactase deficiency, 111

Lactoferrin, 54

exam question on, 149

Lactose, 111

digestion summary for, 112f

Larynx, 21, 22f

Law of intestines, 40–41

Leptin, food intake affected by, 141–142, 141t

LES See Lower esophageal sphincter

Leucine, absorption rates of, 117f, 117t

Lingual lipase, 55

exam question on, 149

Lipase-colipase, 109f

Lithocholic acid, 95, 96f

Liver, bile secretion and functional histology of, 98,98f

Long reflexes See Vagovagal reflex

Longitudinal layer, 30

Lower esophageal sphincter (LES), 23

contraction of, 26, 28

exam question on, 147

manometric recordings of, 24f

tonic contraction between swallows of, 28

transient relaxation of, 26

Lubrication, 54, 63

Luminal/cavital digestion, 109

Lysozyme, 54

M

Maltase, 109f

Maltose, 111

digestion summary for, 112f

Maltotriose, digestion summary for, 112f

Mass movement, 49, 49f

Melanocortin, 140, 140f

Membrane digestion, 109

Micelles, 96, 97f, 121

Migrating motor complex (MMC), 36, 36f, 41–42,42f–43f

MLCK See Myosin light chain kinase

MLCP See Myosin light chain phosphatase

MMC See Migrating motor complex

Monoglyceride acylation pathway, 122–123

Monosaccharide malabsorption, 133

Motilin, 2–3, 12b

actions of, 7t, 8

distributions of, 5, 5f

releasers of, 5, 6t

small intestine affected by, 44

Mrp2 See Multidrug resistance protein 2

Mucosa

gastric

divisions of, 65, 65f

pits and glands of, 65, 65f

transport processes in, 67f

gastrointestinal

hormones released from, 1–2

growth of, 77–80

diet with polyamines in, 78

gastrin as regulator in, 77

small intestine partial resection with, 77–78

pyloric gland, 65, 65f

Mucosal membrane, absorption with, 109–110, 110f

Mucus, 54

gastric juice with, 64

stomach acid secretion with, 77

Multidrug resistance protein 2 (Mrp2), 100

Muscles See also Smooth muscle

exam question on, 147

gastrointestinal tract regulation by, 13–20

striated, 14f, 16–17, 20

Myenteric plexuses, 14, 15f, 39

Myoepithelial cells, 55, 56f

Myosin light chain kinase (MLCK), 18f

Myosin light chain phosphatase (MLCP), 18f

N

Na+ See Sodium

Na+ taurocholate cotransporting polypeptide(NTCP), 100

NaCl See Sodium chloride

Nasopharynx, 21, 22f

Nervous system, 13–20

autonomic (See Autonomic nervous system)

enteric, 14, 15f, 20

esophagus innervation, 25, 26f

extrinsic, 13, 14f–15f, 20

food intake affected by, 140–141, 144

enteric nervous system, 140–141

hypothalamus, 140, 140f

vagus nerve, 140–141

gastrointestinal tract regulation by, 13–15, 14f–15f

salivary glands' innervation, 55–56, 57f

small intestine innervation, 39–40

stomach innervation, 30

Neurocrines, 1, 12b

ANS, 14–15

GI peptides acting as, 9–10

physiological function in gut of, 9–10, 9t

Neuropeptide Y (NPY), 140, 140f

small intestine innervation with, 39–40

Neurotransmitters

exam question on, 146

smooth muscle with, 16–17, 17f

Niacin, 125t

Nitric oxide (NO)

exam question on, 146

interneuron localization of, 14–15

large intestine with, 48

NO See Nitric oxide

Nonspecific esterase, 121

Norepinephrine, 14–15

exam question on, 146

NPY See Neuropeptide Y

NTCP See Na+ taurocholate cotransporting polypep-tide

Nucleus tractus solitarius, 140–141, 144

O

OATPs See Organic anion transport proteins

Obesity, prevalence of, 139, 144

Oblique layer, 30

Obstruction

bile ducts and gallbladder, 104b–105b

idiopathic pseudo-, 45b

Orad portion, 26, 27f

Orad region contractions, 31

Organic anion transport proteins (OATPs), 100

Oropharynx, 21, 22f

Osmotic diarrhea, 133, 134b

exam question on, 153

OXM See Oxyntomodulin

Oxyntic gland area, 65, 65f

Oxyntic glands, mechanisms for inhibiting acid se-cretion in, 75f

Oxyntomodulin (OXM)

food intake affected by, 143–144

P

PACAP See Pituitary adenylate cyclase–activatingpeptide

Pancreas

anatomy of, 82–83

tumors, 91b–92b

Pancreatic lipase, 120, 121f

Pancreatic polypeptide, 8–9, 8t

Pancreatic secretion, 82–93

acinar cells in, 82

aqueous component in, 82–83

centroacinar cells in, 82

clinical applications with, 91b–92b

ductule cells in, 82

electrolytes in, 83–84, 84f–85f

enzymatic/protein component in, 82

enzymes in, 84–86, 86f, 92

exam question on, 150–151

fluids in, 83–84

islets of Langerhans in, 82

potentiation with, 89, 90f

protein component in, 82

regulation of, 86–89

cephalic phase, 86, 87f, 92

gastric phase, 87

intestinal phase, 87–89, 88f, 90f, 92

response to meal with, 90–92

Pancreatitis, 116

Pancreozymin, 2–3 See also Cholecystokinin

Paneth cells, 108

Pantothenic acid, 125t

Paracellular pathways, 129

Paracrines, 1, 10–12, 12b

Parasympathetic innervation, 13, 14f–15f

Parietal cells, 65, 65f

exam question on, 150

Parotid glands, 55

Passive diffusion, 110

Pepsin, 109f

ACh as stimulant to secretion of, 76

gastric juice with, 64

gastrin as stimulant to secretion of, 76

stomach acid secretion with, 75–76, 76f, 81

stomach ulceration with, 76

Pepsinogen, 65

Peptic/chief cells, 65, 65f

hydrochloric acid secrete by, 65

Peptidases, 109f

Peptide YY (PYY), 8t, 9

food intake affected by, 142

Peptides

actions of GI, 2

clinical applications of GI, 11b

clinical tests for GI, 11b–12b

gastrointestinal regulation by, 1–12

neurocrines acting as, 9–10

Peristalsis

esophageal, 23–26, 23f–24f, 26f, 28

pharyngeal, 21–22, 22f–23f

primary, 25

secondary, 25–26

Peristaltic contraction, 21, 22f, 28

caudad region, 31, 31f

Peristaltic reflex, 44

Pharyngeal phases of swallowing, 21–22

anatomy of, 21, 22f

control of peristalsis during, 23f

Pharynx, 21, 22f–23f

exam question on, 147

Phasic contractions, 17

Phosphatidic acid pathway, 123–124

Phospholipase A2, 120–121

Phospholipids, 96–97, 119

bile secretion of, 100

Pituitary adenylate cyclase–activating peptide(PACAP), 10

Potassium (K+), 67–68

absorption of into colon of, 132f

biliary system with, 95f

liver and gallbladder bile concentration of, 102,104t

pancreatic secretion of, 83, 84f–85f

Potentiation

gastric secretion with, 69–70

pancreatic secretion with, 89, 90f

Primary peristalsis, 25

Procarboxypeptidases A and B, 115–116, 116f

Proelastase, 115–116, 116f

Protection, 54, 63

Protein component

pancreatic secretion with, 82

Proximal duodenum, gastric emptying, contractionsin, 34

Ptyalin, 54–55

exam question on, 149

Pyloric gland area, 65, 65f

Pyloro-oxyntic reflex, 72

Pyloroplasty, 37b

Pyloropyloric reflex, 72

Pylorus, 30–31

Pyridoxal See Vitamin B6

Pyridoxamine See Vitamin B6

Pyridoxine See Vitamin B6

PYY See Peptide YY

R

RBCs See Red blood cells

Receptive relaxation, 26–28, 27f

Rectosphincteric reflex, 50, 50f

Rectum, 47, 48f

motility of, 50, 50f

Red blood cells (RBCs), 100, 101f

Regulation

absorption, 113–114

food intake, 139–145

gastric emptying, 35, 34–38, 35f

gastrointestinal tract

hormones in, 1–12

nervous system in, 13–15, 14f–15f

neurohumoral, 16

peptides in, 1–12

muscles, 13–20

nerves, 13–20

pancreatic secretion, 86–89

cephalic phase, 86, 87f, 92

gastric phase, 87

intestinal phase, 87–89, 88f, 90f, 92

peptides, gastrointestinal, 1–12

salivary glands, 61–63, 62f

Relaxation, 19–20

Retropulsion, 31–32

Riboflavin See Vitamin B2

S

Saliva

antibacterial actions of, 54

composition of, 56–61

inorganic, 56–60, 58f–61f

organic, 60–61

electrolytes in, 58, 58f

enzymes in, 54–55

exam question on, 149

functions of, 54–55, 63

ion concentrations in, 58–59, 58f

osmolality of, 58

unique properties of, 56

volume production of, 54, 63

Salivary glands, 54–63

anatomy of, 55–56, 56f

blood supplied to, 56

clinical correlation with, 62b–63b

innervation in, 55–56, 57f

ion movements in, 59–60, 59f–61f

microscopic structure of, 55, 56f

regulation of, 61–63, 62f

Salivon, 55, 56f

Secondary peristalsis, 25–26

Secretin, 2, 12b

actions of, 7–8, 7t

chemistry of, 4, 4f

discovery of, 2

distributions of, 5, 5f

gastric acid secretion inhibition with, 74–75

pancreatic secretion with, 87–89, 88f, 92

releasers of, 6t

Secretory diarrhea, 134b

Segmentation, 40

Serotonin, interneuron localization of, 14–15

Sham feeding, 71

Shunt fascicles, 47–48

Sigmoid colon, 47, 48f

contractions of, 49–50, 49f

Sjögren’s syndrome, salivary glands with, 62b–63b

Slow waves

bottom tracing of, 33f

exam question on, 147–148

gastric emptying with, 32–33, 33f, 38

large intestine, 51, 53

small intestine with, 42, 43f

smooth muscle with, 18–19, 19f

top tracing of, 33f

Small intestine See Intestine, small

Smooth muscle

anatomy of, 16–17, 16f–17f

contractions of, 17–20

biochemistry of, 17–18, 18f

phasic compared to tonic, 17

fasciae of, 16–17

gastric contractions from, 30, 33f

intracellular structural specializations of, 16f

neurotransmitters with, 16–17, 17f

slow waves in, 18–19, 19f

“unitary, ”, 16–17, 17f

Sodium (Na+)

absorption of into colon of, 132f

biliary system with, 95f

liver and gallbladder bile concentration of, 102,104t

pancreatic secretion of, 83, 84f–85f

Sodium chloride (NaCl)

absorption of, 130–131, 130f, 132f

Somatostatin, 10, 73

exam question on, 146

interneuron localization of, 14–15

small intestine innervation with, 39–40

Sphincter of Oddi, 101–102, 103f

Spike bursts, 32

Spike potentials, 18

small intestine with, 42–43, 43f

stomach contractions with, 32

Starch, 111

Starling forces, 128–129

Steatorrhea, 91b–92b

Sterols, 119

Stomach

anatomy of, 30–31

anatomy related to, 65–67, 65f–66f

distention of, 72

divisions of, 26, 27f

emptying of (See Gastric emptying)

gastric secretion in, 64–81

acid in, 67–68, 67f, 81

cephalic phase for, 71, 71f, 81

clinical applications with, 78b–80b, 78t

constituents of, 64

electrical potential difference, origin with, 68

electrolytes in, 68–69, 69f, 80

gastric phase for, 71–73, 72f, 81

gastrin release in, 73, 73f, 81

growth of GI mucosa with, 77–80

histamine's role in, 69–70, 70f

history regarding, 64

inhibition of, 74–75, 75f

intestinal phase for, 73, 74f

intrinsic factor with, 64, 77, 81

mucus in, 77

pepsin in, 75–76, 76f, 81

stimulants of acid in, 69–70, 80

stimulation of, 70–73

ICCs in, 31

innervation of, 30

proximal duodenum of, 31

pylorus of, 30–31

receptive relaxation of, 26–28, 27f

ulceration, pepsin with, 76

Striated duct, 55–56, 56f

Striated duct epithelium, 56

Sublingual glands, 55

Submandibular glands, 55

Submucosal plexuses, 14, 15f

Substance P, 14–15

large intestine with, 48

small intestine innervation with, 39–40

Sucrase, 109f

Sucrose, 111

digestion summary for, 112f

Swallowing, 21–29

chewing before, 21

clinical applications with, 27b–28b

clinical tests for, 28b

defined, 21

esophageal peristalsis phase of, 23–26, 23f–24f, 26f

pharyngeal phases of, 21–22, 22f–23f

stomach involvement in, 26–28, 27f

voluntarily and involuntary aspect to, 21, 28

Swallowing center, 22, 23f

Sympathetic innervation, 13–14, 14f–15f

T

Tachykinins (TKs), 14–15

large intestine with, 48

Taeniae coli, 47, 48f

Thiamine See Vitamin B1

Tight junctions/zonulae occludens, 129

TKs See Tachykinins

Tongue, 21, 22f

exam question on, 147

Tonic contraction

LES with between swallow, 28

phasic compared, 17

Top tracing, 33f

Transcellular pathways, 129

Transport See Absorption

Transverse colon, 47, 48f

Trehalase, 109f

Trehalose, digestion summary for, 112f

Triglyceride, digestion and absorption of, 122f, 124

Triglycerides, 119

Trypsin, 109f

Trypsinogen, 115–116, 116f

Tumors of pancreas, 91b–92b

U

UES See Upper esophageal sphincter

Unstirred layer of fluid, 109–110

Upper esophageal sphincter (UES), 21, 22f–23f

exam question on, 147

V

Vagal afferents, 140–142, 141t

Vagotomy, 25

gastric emptying of solids with, 37b, 38

Vagovagal reflex, 13, 27

stomach acid secretion with, 72

Vagus nerve, food intake affected by, 140–141

Vasoactive intestinal peptide (VIP), 4, 4f, 9–10, 9t,12b

exam question on, 146

interneuron localization of, 14–15

large intestine with, 48

VIP See Vasoactive intestinal peptide

Vitamin A, 125t, 126

Vitamin B1 (Thiamine), 125, 125t

Vitamin B2 (Riboflavin), 125t

Vitamin B6 (Pyridoxine, Pyridoxal, Pyridoxamine),125t

Vitamin B12, 125–126, 125t

Vitamin C (Ascorbic acid), 125, 125t

Vitamin D, 125t, 126, 135, 138

Vitamin E, 125t, 126

Vitamin K, 125t, 126

Vomiting (Emesis), 44–46

defined, 44

induction of, 45

problems with prolonged, 45

reverse peristalsis with, 44

W

Water (H2O)

absorption or secretion of, 131–133, 133f

bile secretion of, 100–101, 102f

biliary system with, 95f

pancreatic secretion of, 83, 84f

Z

Zollinger-Ellison syndrome, 11b–12b

exam question on, 146

Zonulae occludens, 129

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