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NROSCI/BIOSC 1070 and MSNBIO 2070September 8, 2017

Neural Control of Physiological Mechanisms

Aswewillexploreduringthenexttwolectures,thenervoussystemhasprofoundinfluencesonphysiological processes in the body. There are two principal ways through which the nervous system caninfluencephysiology:viathereleaseofbloodbourne-hormonesfromthepituitaryglandandviatwo systems of neurons (that are part of the autonomic nervous system) whose axons leave the central nervous system. The autonomic nervous system controls all visceral functions of the body. This system helps control arterial pressure, gastrointestinal motility and secretion, urinary bladder emptying, sweating, body temperature, and many other activities. Some of these functions are controlled exclusively by the autonomic nervous system, and others are only partially regulated through the autonomic nervous system. Why is the nervous system involved in physiological regulation? First, the nervous system can predict future events that require physiological adjustments, and trigger these alterations so they are in place when needed. For example, when an animal or human detects a potentially harmful environmental situation, heart rate and blood pressure increases, the pupils widen, and piloerection occurs to prepare for a“fightorflight”response.Second,thenervoussystemcanelicitspecificreflex-mediatedadjustmentsin physiological processes in response to particular afferent inputs. For example, a drop in blood pressure issignalledbyadropinfiringofbaroreceptorafferents,whichelicitsareflex-mediatedincreaseinheart rate and peripheral vasoconstriction to restore blood pressure to normal values. The entire nervous system participates in producing physiological adjustments, although particular regions have a paramount role. The nervous system regions that are most involved in physiological regulation include the hypothalamus, which is located in the diencephalon, as well as several areas of thebrainstem,mainlyfoundinthemedulla,Thehypothalamushaschemicalinfluencesonthepituitarygland, as we will see in the next lecture, and thus is the nervous system region most involved in control of hormonal release. Furthermore, the hypothalamus integrates inputs from a number of neural regions, andprovidesinfluencesonbrainstemregionsinvolvedinautonomiccontrol.

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Efferent autonomic signals are transmitted to the body through two major subdivisions of the autonomic nervous system called the sympathetic nervous system and the parasympathetic nervous system. A third division of the autonomic nervous system is the enteric nervous system, which controls activityinthegastrointestinaltract.Autonomicoutflowfromthecentralnervoussystemisthroughspinalnervesaswellasspecificcranialnerves,aswillbediscussedbelow.Inaddition,anumberofintegrativeregionsofthebrainsteminfluenceautonomicoutflow.Forexample,aportionofthereticularformation of the rostral ventrolateral medulla plays an important role in controlling the excitability of agroupofsympatheticnervoussystem“output”neuronsinthethoracicspinalcord,particularlythosesympathetic neurons that are involved in cardiovascular regulation. Another region of the brainstem with an important role in autonomic regulation is nucleus tractus solitarius (NTS), which is located in the dorsomedial portion of the caudal medulla. Nucleus tractus solitarius receives inputs from a variety of types of visceral afferents, including those innervating large blood vessels, the lungs, the gastrointestinalsystem,etc.Thus,mostreflex-mediatedadjustmentsinautonomicfunctioninvolveNTS. The location of NTS is shown below.

Solitary Nucleusand TractNucleus

Ambiguus

Dorsal Motor Nucelusof the Vagus

Hence, damage to the cervical spinal cord can have devastating effects on autonomic regula-tion.Ifthecervicalspinalcordistransected,brainsteminputstoallsympatheticoutputneuronsandthe subset of parasympathetic output neurons in the sacral spinal cord are lost. This abolishes control of blood pressure by the sympathetic nervous system, bladder control, etc. As a result, patients with spinal cord transections have serious problems in physiological regulation.

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We will devote the rest of this lecture considering the organization of the autonomic nervous system.GENERAL ORGANIZATION OF PERIPHERAL PORTIONS OF THE SYMPATHETIC AND PARASYMPATHETIC SYSTEMS

Unlike in the somatic motor system, where the axon of a motoneuron in the spinal cord or brainstem innervates skeletal muscle, two neurons comprise the peripheral portions of the sympathetic and parasympathetic nervous systems. The axon of a preganglionic neuron, whose cell body resides in the central nervous system, makes a synapse on a postganglionic neuron whose cell body is located in a ganglion in the periphery. The axon of the postganglionic neuron innervates the peripheral target, which typically is smooth or cardiac muscle.

The somata of efferent sympathetic preganglionic neurons are located in the intermediolateral cell column (or intermediolateral horn) of the thoracic and upper lumbar spinal cord. The axon of this neuronpassesthroughtheventral(anterior)root,tojointhespinalnerve.Immediatelyafterthespinalnerveleavesthespinalcanal,thepreganglionicsympatheticfibersleavethenerveandpassthroughthewhite ramus into one of the ganglia of the sympathetic chain.Thenthecourseofthefibercanbeoneofthefollowingthree:1)itcansynapsewithpostganglionic neurons in the ganglion that it enters; 2) it can pass upward or downward in the chain and synapse with a postganglionic neuron in one of the other ganglia of the chain; 3) it can pass for variable distances through the chain, and then through one of the sympathetic nervesradiatingoutwardfromthechain,finallyterminatinginoneoftheprevertebral ganglia.Thus,thecellbodiesofsympatheticpostganglionicneuronshavetwolocations:gangliaofthesympathetic chain (also called paravertebral ganglia) and prevertebral ganglia located in the periphery. The axons of postganglionic neurons innervate peripheral targets, such as smooth muscle of the gut wall or in arterioles. Somepostganglionicfibersarisingfromparavertebralgangliapassbackfromthesympatheticchain into the spinal nerves through gray rami at all levels of the spinal cord. These postganglionic fiberstraveltoallpartsofthebodyintheskeletalnerves.Suchfibersinnervatetargetssuchassmoothmuscleinarterioles,sweatglands,andpiloerectormusclesofthehairs.About8%ofthefibersintheaverageskeletalnervearepostganglionicfibers,whichindicatestheirgreatimportance.

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The adrenal medulla is a special target of sympathetic efferents. Preganglionic sympathetic fiberspass,without synapsing, all the way from the intermediolateral cell column of the spinal cord through the sympathetic chain and sympathetic nerves to the adrenal medulla. Cells in the adrenal medulla can be regarded in some ways as postganglionic neurons, as they are derived embryologically from neural tissue. The adrenal medulla is a secretory organ that excretes both norepinephrine and epinephrine into the bloodstream. Incontrasttosympatheticpreganglionicneurons,parasympathetic preganglionic neurons are located in the brainstem (mainly nucleus ambiguus and the dorsal motor nucleus of the vagus) and sacral spinal cord. Parasympathetic preganglionic axons leave the central nervous system through cranial nervesIII,VII,IX,andXandthesacralventralroots. Approximately75%ofallparasympatheticpreganglionicaxonsarelocatedinthevagusnerve(cranialnerveX),andoftenthevagusnerveisequatedwithparasympatheticoutflow.Thevagusnervesuppliesparasympatheticfiberstotheheart,lungs,esophagus, stomach, small intestine, proximal colon, pancreas, and upper portion of the ureters.

ParasympatheticfibersincranialnerveIIIinnervatepupillarysphinctersandciliarymusclesoftheeye.ParasympatheticfibersincranialnerveVIIpasstothelacrimal(secretetears),nasal(secretemucus),andsubmandibularglands(asalivarygland),andfibersincranialnerveIXpasstotheparotidgland (a salivary gland). The sacral parasympathetic nerves distribute parasympathetic preganglionic fiberstothedistalcolon,rectum,bladder,lowerportionoftheureters,andexternalgenitaliatocauseerection.

Output TargetsCN III Sphincter pupillae (mediates pupillary constriction) and the muscles of the

ciliary body (control the shape of the lens)CN VII Salivary glands (except parotid) and the lacrimal and nasal glandsCN IX Parotid glandCN X Nearly all thoracic and abdominal viscera (heart, lungs, esophagus, stom-

ach, small intestine, proximal colon, pancreas, and upper portion of the ureters)

Sacral spinal cord

Distal colon, rectum, bladder, lower portion of the ureters, external genitalia

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Sympathetic Nervous System Parasympathetic Nervous System

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1) Basic pharmacology

Sympatheticandparasympatheticnervefiberssecreteoneortheotheroftwosynaptictransmittersubstances:norepinephrine and acetylcholine.Thosefibersthatsecreteacetylcholinearesaidtobecholinergic, whereas those that secrete norepinephrine are called adrenergic. ALL preganglionic neurons are cholinergic, and release acetylcholine onto postganglionic neurons. All (or at least MOST) postganglionic neurons of the parasympathetic nervous system are also cholinergic. On the otherhand,most(butnotall)postganglionicsympatheticfibersreleasenorepinephrine.Anexceptionarethepostganglionicsympatheticfibersthatinnervatesweatglands,piloerectormuscles,andafewbloodvessels(insomespecies),whicharecholinergic.Asasimplification,acetylcholineissometimescalled the parasympathetic neurotransmitter, whereas norepinephrine is called the sympathetic neurotransmitter.

2) Release of acetylcholine and norepinephrine from postganglionic nerve terminals Although some parasympathetic nerve terminals are like small neuromuscular junctions, many parasympatheticnervefibersandmostsympatheticnervefibersdonotformcloseconnectionswith

The parasympathetic nervous system, like the sympathetic nervous system, is comprised of both preganglionic and postganglionic neurons, The major difference is that in the parasympathetic system, the postganglionic neuron is typically embedded in the target organ. The preganglionic neuron axon courses all the way into the periphery, to innervate the postganglionic neurons, whose short axons in turn innervate the excited organ.

BASIC CHARACTERISTICS OF SYMPATHETIC AND PARASYMPATHETIC FUNCTION

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theirtargets.Instead,thepostganglionicnervefibersformbulbousswellings,calledvaricosities, which are located in proximity to the effector cells. These varicosities contain the transmitter substances. Transmission in the autonomic nervous system is similar to that elsewhere in the nervous system. When anactionpotentialspreadsovertheterminalfibers,thedepolarizationincreasesthepermeabilityofthefibermembraneforcalcium,allowingthisiontoenterthefiber.Afterenteringthefiber,calciumcauses secretory vesicles near the membrane to fuse with the membrane and empty their transmitter substance to the exterior.

AcetylcholineissynthesizedfromAcetyl-COAandcholine,inareactionthatiscatalyzedbycholine acetyltransferase. Once acetylcholine is released into the periphery, it is inactivated by the enzyme acetylcholinesterase, as at the neuromuscular junction.

Norepinephrine is synthesized as shown below. The transmitter epinephrine, which is released from the adrenal medulla, is synthesized from norepinephrine. After secretion from terminal nerve endings,norepinephrineismainlyinactivatedthroughreuptakeintonervefibers;thisprocessoccursvery rapidly. However, the norepinephrine and epinephrine released from the adrenal medulla into the blood remain active until they diffuse into tissue, where they are inactivated by degradation by catechol-O-methyltransferase.Mostofthisinactivationoccursintheliver.Asaresult,epinephrineandnorepinephrinereleasedintothebloodcanexerteffectsforarelativelylongtimecourse:manyseconds to over a minute.

3) Actions of acetylcholine and norepinephrine on effectors

Acetylcholine and norepinephrine, like almost all transmitter substances, exert their effects throughbindingtoaspecificreceptorlocatedonthecellmembrane.Therearetwogeneralmechanismsthrough which ligand binding can produce an effect in the target cell. One mechanism is to cause a conformationalchangeinaspecifictypeofreceptor,alteringthepermeabilityforparticularions.Anothermechanism is to produce activation of an enzyme, which results in the formation of second messengers. A good example of an enzyme that is activated by ligand binding is adenylcyclase, which promotes the formationofcAMPintracellularly.Inturn,cAMPcanphosphorylateanumberofdifferentenzymes,thereby activating them. Thus, the intracellular effects of cyclic nucleotides depends on the enzymes presentinthecell.Inmanycases,G-proteins located in the membrane link membrane receptors to eitherligandchannelsormembrane-boundenzymes.G-proteinsgettheirnamebecausetheyallbindGTP.

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4) Types of acetylcholine receptors

There are twomajor subtypesof acetylcholine receptors:nicotinic and muscarinic. These receptors are named as such because muscarinic receptors are activated by muscarine, a poison from toadstools, whereas nicotinic receptors are activated by nicotine. Nicotinic receptors are located within theneuromuscularjunction,aswellasinautonomicganglia. Incontrast,muscarinicreceptorsarelocated at the junction between parasympathetic postganglionic neurons (and cholinergic sympathetic postganglionic neurons) and their targets. Although both nicotinic and muscarinic receptors have the same endogenous ligand, acetylcholine, their mechanism for eliciting intracellular effects are completely different.Activationofnicotinicreceptorsresultsintheopeningofspecificcationchannels,whereasactivationofmuscarinicreceptorselicits intracellulareffects thataremediatedthroughG-proteins.TheseG-proteins,inturn,arelinkedtoenzymesthatproducesecondmessengersortogatedpotassiumchannels. There are subtypes of muscarinic and nicotinic receptors, and drugs may only bind to one specificsubtype.Forexample,thedrugcurare,whichblocksthenicotinicreceptorattheneuromuscularjunction, has little effect on nicotinic receptors in autonomic ganglia.

Location Agonists AntagonistsNeuromusclar

Junctionacetylcholine

carbacholsuxamethonium

curarepancuroniumα-conotoxin

α-bungarotoxinAutonomicGanglia

acetylcholinecarbacholnicotine

epibatidine

mecamylamineα-bungarotoxinhexamethonium

Brain acetylcholinenicotine

epibatidine

α-conotoxinmecamylamine

Subtypes of nicotinic receptors:

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5) Types of norepinephrine receptors

Therearetwomajorsubclassesofnorepinephrinereceptors,whichcanbeaffectedbyspecificdrugs:alphaandbeta.Inaddition,bothalphaandbetareceptorscanbefurtherdividedintosubtypesbased on pharmacological sensitivity. The targets of postganglionic sympathetic neurons contain α

1, α

2,

β1, and β

2 receptors.Differenttypesofthesereceptorshavedifferentrelativeaffinitiesfornorepinephrine

andepinephrine(whichisreleasedfromtheadrenalmedulla),asshowninthefollowingtable:

α1/α

2receptors: NE>E

β1 receptors: NE=E

β2receptors: E>NE

Activation of all adrenergic receptors initiates a second messenger cascade. Activation of alpha receptors causes the activation of phospholipase C, which induces the opening of calcium channels on the cell surface or the release of calcium from intracellular stores. The increased intracellular calcium inducesmusclecontraction.Incontrast,bindingofagonisttobetareceptorscausestheactivationofcAMP, and the phosphorylation of intracellular proteins.

6) Peripheral distribution of adrenergic and cholinergic receptors, and the effects of receptor activation

The tables on the next two pages describe the locations of adrenergic and cholinergic receptors in many organ systems, and the effects of binding of ligand to these receptors. The nature of this course requiresthatyouMEMORIZEthistable.Unlessyouknowthisinformation,youwillbeunabletounderstand physiology.

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EffectorOrgan

Sympathetic Effect ParasympatheticEffectReceptor

Heart, SA Node β1Increaseinheartrate Decrease in heart rate

Atria β1Increaseincontractility Decrease in contractility

AVNode β1Increaseinconduction

velocityDecrease in conduction

velocityHis-PurkinjeSystem β1

Increaseinconductionvelocity NONE

Ventricles β1Increaseincontractility NONE

Arterioles, Coronary β2

Dilation Dilation

Skin & Mucosa α1 α2Constriction NONE

Skeletal Muscleα1 α2

ConstrictionNONE

β2Dilation

AbdominalViscera

α1Constriction

NONEβ2

Dilation (mainly in liver)

SalivaryGlands α1 α2Constriction Dilation

Kidney α1 α2Constriction NONE

Veins α1 α2Constriction NONE

Cardiovascular System Receptors

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EffectorOrgan

Sympathetic Effect ParasympatheticEffectReceptor

Eye, Radial Muscle α1Contracts (pupil widens) NONE

Sphincter Muscle NONE Contracts (pupil closes)

Ciliary Muscle β2Relaxation (flattens lens

for far vision)Contraction (lens becomes

more convex)Lungs, Bronchial

Muscle β2Relaxation Contraction

BronchialGlandsα1

Decreased SecretionIncreasedSecretion

β2IncreasedSecretion

GISystem, Smooth Muscle in Wall α1 α2 β1 β2

Relaxation (relatively weak)

Contraction (effect MUCH stronger)

Sphincters α1Contraction Relaxation

GallbladderandDucts β2Relaxation Contraction

Urinary Bladder, Wall β2Relaxation Contraction

Sphincter α1Contraction Relaxation

Skin, Pilomotor Mus-cles ACH Contraction (piloerection)

NONESweatGlands

α1Secretion (certain sites

only, e.g. palms)

ACH GeneralizedSecretion

Skeletal Muscle β2IncreasedContractility NONE

Other Receptors

7) Role of the adrenal medulla in autonomic control

By activating preganglionic neurons innervating the adrenal medulla, the sympathetic nervous systeminducesareleaseofbothepinephrineandnorepinephrineintothebloodstream.Generally,about80% of the secretion from the adrenal medulla is epinephrine, whereas only 20% is norepinephrine. However, the sympathetic nervous system has appropriate flexibility to increase the fraction ofnorepinephrine released when appropriate. Circulating norepinephrine and epinephrine bind to the same receptors as those affected by norepinephrine released from postganglionic sympathetic nerve terminals.

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However,circulatingcatecholaminestake5-10timesaslongtoremoveasthosereleasedfromnerveterminals. Thus, activation of the adrenal medulla will result in a prolonged autonomic response. Furthermore,becauseepinephrinehasamuchstrongeraffinityforbetareceptorsthanalphareceptors,this transmitter will produce slightly different effects. For example, epinephrine induces a large increase inheartrateduetobeta-receptorbinding,buthaslittleeffectonvasoconstrictioninmostvascularbedsbecause this effect is mediated through alpha receptors. Finally, circulating epinephrine can affect cellsthatarenotinnervatedbythesympatheticnervoussystem.Infact,epinephrineactstoincreasemetabolic activity in almost every cell of the body.

REGULATION OF AUTONOMIC OUTFLOW Activity in the sympathetic and parasympathetic nervous systems would be negligible unless preganglionic neurons receive substantial synaptic inputs. Sympathetic preganglionic neurons in the spinal cord receive inputs from spinal interneurons, and stimulation of either visceral or somatic afferents entering the spinal cord can induce changes in activity in both sympathetic preganglionic neurons and postganglionic neurons. However, the predominant inputs to sympathetic preganglionic neurons comefromthebrainstem.Substantialresearchoverthepastfewyearshasdefinedthefollowingmajorbrainstemareasthatprovidedirectinputstosympatheticpreganglionicneurons:

1) the reticular formation of the rostral ventrolateral medulla 2) the midline medullary raphe nuclei 3) the reticular formation of the ventromedial medulla 4) the paraventricular nucleus of the hypothalamus

Other brainstem regions also participate in autonomic control, as they regulate the activity of spinally-projectingbrainstemneuronsthatmakesynapticconnectionswithsympatheticpreganglionicneurons. We will consider each of these brainstem regions and their role in autonomic control during the course.

Parasympathetic preganglionic neurons located in the sacral spinal cord also receive inputs from spinal cord circuits and descending pathways from the brainstem. Parasympathetic preganglionic neurons located in the brainstem also receive inputs from selected brainstem regions, as we will discuss at relevant times during the course.

FUNCTIONS OF THE AUTONOMIC NERVOUS SYSTEM1) Maintenance of baseline tone

Sympatheticandparasympathetic systemsare tonicallyactive,producingabaseline“tone”intheirtargets.Forexample,tonicactivityinsympatheticpostganglionicfibersinnervatingvascularsmooth muscle helps to maintain baseline blood pressure, and provides for the possibility of vasodilation through removal of sympathetic activity.

2) Maintenance of homeostasis—the classical view

Earlier this century, Walter Cannon proposed a number of theories about autonomic functioning that still persist today. Cannon’s view was that the parasympathetic and sympathetic nervous systems

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worked together in an antagonistic fashion to achieve homeostasis. Predominance of sympathetic activityputsthebodyinto“fightorflight”mode,whereaspredominanceofparasympatheticactivityputsthebodyinto“restanddigest”mode.Thesympatheticnervoussystem,inCannon’sview,workedvia“massdischarge.”Inotherwords,allsympatheticefferentsdischargedtogetherduringstressfulsituationsinordertoelicitaglobalresponse.Anyspecificityinautonomicactionwasduetotheactionsof the parasympathetic nervous system, which (according to Cannon) differed from the sympathetic systeminbeingcapabletoproduceeffectsinspecifictargets.

Insomeregards,Cannon’sviewofthesympatheticnervoussystemhasmerits.Reviewofthetable above indicates that the sympathetic and parasympathetic nervous systems have antagonistic actions on some, but certainly not all, targets. Furthermore, during some situations in which an environmental stressoccurs,manysympatheticefferentsdischargeinsynchronytohavethefollowingeffects:

1)Increasedarterialbloodpressure2)Increasedbloodflowtoactivemuscles,concurrentwithreducedbloodflowtoorgans

(e.g.kidneyandGItract)thatarenotrequiredformuscularactivity3)Increasedratesofcellularmetabolismthroughoutthebody4)Increasedbloodglucoseconcentration5)Increasedglycolysisintheliverandmuscle6)Increasedmuscularstrength7)Increasedrateofbloodcoagulation.

3) Maintenance of homeostasis—the modern view

Recent studies have shown that control of the sympathetic nervous system can be much more precise than Cannon envisioned. Particular stimuli are now known to activate only certain sympathetic efferents. For example, distension of the gastrointestinal tract results in activation of sympathetic preganglionic neurons that innervate the gut, but not those that innervate targets such as blood vessels and sweat glands. Furthermore, during particular activities a “patterned” response that involvesactivation of some sympathetic preganglionic neurons and inhibition of others occurs. This patterning ofsympatheticoutflowinsuresthatappropriateautonomicadjustmentsoccursothathomeostasiswilloccurduringparticularmotortasksorenvironmentalperturbations.Thebottomline:activityinthesympatheticnervoussystemcanbefinelycontrolledbycentralnervoussystemcircuits.

SOME CAVEATS So far we have only considered release of acetylcholine and norepinephrine from sympathetic andparasympatheticpre-andpost-ganglionicneurons.However,“non-adrenergic, non-cholinergic” neurotransmission also appears to occur in the autonomic nervous system. For example, many peptide transmittersubstances(e.g.,neuropeptideY,VIP)co-existwithacetylcholineandnorepinephrineinpreganglionicandpostganglionicneurons. It isbelieved that releaseof these substancesplaysanimportant role in modulating the effects of the principal transmitters.

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DRUGS THAT AFFECT AUTONOMIC TRANSMISSION A number of drugs can affect the autonomic nervous system. Some examples are listed in the table below.

Drugs that potentiate transmitter action at synaptic terminalsEphedrine, Amphetamine potentiate NE release Neostigmine inhibit acetylcholinesterase action

Drugs that prevent neurotransmitter releaseReserpine prevents synthesis and storage of NEGuanethidine preventsNEreleasefromnerveterminals

Drugs that are agonists or antagonists for particular receptorsEffectClonidine α2 agonist Isoproterenol β agonist Albuterol β2 agonistPhenylephrine α1 agonist Prazosin α1 antagonist Propranolol β antagonistMetoprolol β1 antagonist α-Yohimbine(Rauwscoline) α2 antagonist

Nicotine nicotinic receptor agonistPilocarpine, Metacholine muscarinic receptor agonistHexamethonium nicotinic receptor antagonist (ganglionic blocker)Atropine, Scopolamine muscarinic receptor antagonist

Clinical Note--Mode of Action of Viagra OneofthemostprescribeddrugsintheworldisViagra(genericnameissildenafilcitrate),which causes penile erection in males by producing vasodilation of blood vessels in the penis. What is the mechanism of action of this drug?

It has been known formany years that some nitrogen-containing compounds, such asnitroglycerin, can produce vasodilation (e.g., nitroglycerin is administered to patients with heart disease to elicit vasodilation of heart blood vessels thereby enhancing blood delivery to cardiac muscle). Over the past two decades, it was proven that a gaseous transmitter substance in the body, nitric oxide (NO), isapotentendogenousvasodilator.Thisunchargedsolublegashasahalf-lifeof2-30secondsandis rapidly broken down in the body. NO is produced in the endothelial lining of blood vessels, and diffuses into adjacent smooth muscle cells of the vessel, causing the smooth muscle to relax and resulting in vasodilation. For many years scientists were unconvinced that NO could be used as a signalling molecule by the body, as this gas is very toxic to cells when in high concentrations. Overwhelming scientificevidencehassinceprovenotherwise.Inadditiontoservingasavasodilator,NOisusedasa neurotransmitter by certain nerve cells.

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ACH

Endo

thel

ial

Cel

l

NO

Smoo

th M

us-

cle

Cel

lParasympatheticNerve Terminal

Blood vessels in the genitalia are amongst a few in the body that are innervated by the parasympathetic nervous system. Release of acetylcholine onto endothelial cells of genital arterioles results in the release of nitric oxide by these cells, which diffuses into the adjacent smooth muscle and produces relaxation and thus vasodilation. NO produces smooth muscle relaxation by activating the enzyme guanylate cyclase, which resultsinincreasedlevelsofcyclicguanosinemonophosphate(cGMP).Thisintracellularmessengeractivates an ATPase that pumps calcium out of the smooth muscle cell, thereby inhibiting interactions between actin and myosin.

Sildenafilcitratehasthefollowingstructuralformula:

Sildenafilhasnodirectrelaxanteffectonisolatedhumancorpuscavernosum,butenhancestheeffect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradationofcGMPinthecorpuscavernosum.WhensexualstimulationcauseslocalreleaseofNO,inhibitionofPDE5bysildenafilcausesincreasedlevelsofcGMPinthecorpuscavernosum,resultinginsmoothmusclerelaxationandinflowofbloodtothecorpuscavernosum.Sildenafilatrecommendeddoses has no effect in the absence of sexual stimulation.

StudiesinvitrohaveshownthatsildenafilisselectiveforPDE5.ItseffectismorepotentonPDE5thanonotherknownphosphodiesterases(>80-foldforPDE1,>1,000-foldforPDE2,PDE3,andPDE4).Theapproximately4,000-foldselectivityforPDE5versusPDE3isimportantbecausethatPDEisinvolvedincontrolofcardiaccontractility.Sildenafilisonlyabout10-foldaspotentforPDE5compared to PDE6, an enzyme found in the retina; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels.

In addition to human corpus cavernosum smoothmuscle, PDE5 is also found in lowerconcentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle.TheinhibitionofPDE5inthesetissuesbysildenafilmaybethebasisfortheenhancedplateletantiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation invivoandperipheralarterial-venousdilatationinvivo.

Clinical Note: “Female Viagra”

YoumayhaveheardrecentnewsthattheFDAisconsideringtheapprovalof“femaleviagra”tocounteract“hypoactivesexualdesiredisorder.”Thenamingofthedrugbythepressisunfortunate,sinceitiscompletelydifferentfromSildenafil.Thenewdrugis“Flibanserin,”whichactsondopamineandserotonin receptors in the brain. The full report submitted to the FDA to request approval of Flibanserin is available on the course website, at this link.