effects of electrical stimulation and lesions of …

EFFECTS OF ELECTRICAL STIMULATION AND LESIONS OF ROSTRAL FASTIGIAL

NUCLEUS ON BARORECEPTOR SENSITIVITY AND AUTONOMIC RESPONSES

TO TRANSIENT CHANGES IN ARTERIAL BLOOD PRESSURE

by

CHU-HUANG CHEN, B.Med.

A DISSERTATION

IN

PHYSIOLOGY

Submitted to the Graduate Faculty of Texas Tech University Health Sciences Center

in Partial Fullfilment of the Requirements for

the Degree of

DOCTOR OF PHILOSOPHY

Approved

August, 1986

1'3

c-T ACKOWLEDGEMENTS

I am indebted to my advisor, Dr. Lorenz 0. Lutherer, for his

guidance, advice, and unfailing patience during my graduate years. I

thank him for his time and support in helping me complete this

project. His instruction has been inspiring and invaluable.

I am indebted also to the other members of my committee, Drs.

Michael T. Kopetzky, Donald G. Davies, Herbert F. Janssen, and Jean

C. Strahlendorf, for their suggestions and criticism of my research.

I am grateful to Randal Pierce, for writing the computer program and

other helps in electronics; Pam Robinson, for technical assistance;

Debbie Parker, for preparing the figures; Janis Files, for aid in

statistical analysis; Judith Keeling, for literary critiques; and

Jack Williams for sharing the information and experience. The

tireless love and support of my wife, Tsing, have comforted me in all

events through my graduate years. Her partnership will continue to

serve as inspiration in my future endeavors. I am thankful to Tarbox

Parkinson's Disease Institute, Texas Tech University Health Sciences

Center for supporting this project.

I would like to dedicate this dissertation to my father and my

late mother, Mr. and Mrs. Kao-Long Chen. The completion of this

project would be fully rewarded if my mother, Shiou, who was

anticipating attending my graduation, were with us still.

11

TABLE OF CONTENTS

ACKNOWLEDGEMENTS ii

LIST OF TABLES v

LIST OF FIGURES vi

LIST OF ABBREVIATIONS viii

CHAPTER

I. INTRODUCTION 1

Statement of Purpose 1

Anatomy of the Cerebellar Fastigial Nucleus 2

Historical Development of Cerebellar and Fastigial

Physiology 8

Effects of Stimulation and Lesions of rFN on Cardiovascular Responses 15

Effects of rFN Stimulation on Baroreflexes and the Autonomic Output 21

Effects of rFN Lesions or Cerebellectomy on Cardiovascular Responses to Hypotensive Challenges 25

Background for the Dissertation Research 29

II. MATERIALS AND METHODS 34

General Preparation of the Cats 34

Blood Pressure, Heart Rate, and Blood Flow

Monitoring 35

Administration of Drugs 36

Stimulation and Lesion 36

iii

Histology 37

Protocol and Statistical Analysis 38

III. RESULTS 43

Part I. Influence of rFN Stimulation on Cardiac Parasympathetic Activity 43

Part II. Effects of Bilateral rFN Lesions on Baroreceptor Sensitivity and Cardiovascular Responses to Transient Hypotension 64

IV. DISCUSSION 84

Part I. Stimulation of rFN Inhibits Parasympathetic Activation Induced by Elevated MAP . . . 84

Part II. Bilateral rFNL Impair Cardiovascular Responses to Transient Hypotension and Alter Baroreceptor Sensitivity 89

General Discussion 95

REFERENCES 107

IV

LIST OF TABLES

1. Protocol in Part I 39

2. Protocol in Part II 41

3. Effect of Propranolol on MAP and HR at Rest and Their Maximal Changes During Treatments with rFNS alone, PE Infusion alone, and Combination of rFNS and PE Infusion 46

4. Influence of rFN Lesions on Resting MAP and HR 68

5. Maximal MAP and HR Changes Induced by NP Administration Before and After rFN Lesions 69

6. Time Course of MAP Recovery After NP-induced Hypotension in Cats with Lesions of rFN 75

7. Influence of Bilateral rFNL on MAP and HR Responses During Recovery After NP-Induced Hypotension (n = 12) . 76

8. Influences of Bilateral rFNL on MAP, HR, and Femoral R Responses During Recovery After NP-induced Hypotension (n = 6) 77

9. Influences of Captopril on Resting MAP and HR, Maximal Changes in MAP and HR, and Time Course of MAP Recovery After NP Administration 79

10. Effects of Propranolol on Resting MAP and HR, Maximal Changes in MAP and HR, and Time Course of MAP Recovery After NP Administration 80

LIST OF FIGURES

1. Sagittal section of cerebellum and brainstem showing rostrocaudal organization of cerebellum and localization of fastigial nucleus (FN) 3

2. Schematic drawing showing mediolateral organization of cerebellum, cerebellar corticonuclear relationships, and localization of fastigial nucleus (FN) 6

3. Camera lucida drawing of sagittal sections of the cerebellum showing active sites (•) for pressor responses to electrical stimulation in the rostromedial fastigial nucleus 44

4. MAP and HR responses to stimulation of rostromedial fastigial nucleus at 100 vA (rFNS,QQ), 50 Hz, 0.1 msec before propranolol (PPN) aaministration . . . . 49

5. MAP and HR Responses to stimulation of rostromedial fastigial nucleus at 100 HA (rFNS,^^), 50 Hz, 0.1 msec after propranolol (PPN) aaministration . . . 51

6. Effects of propranolol (PPN) on changes in mean arterial pressure (MAP) (upper panel), and change in heart rate (HR) (lower panel) in response to rFNS 53

7. Effect of propranolol (PPN) on change in HR per unit change in MAP in response to phenylephrine (PE) infusion alone, or in combination with rFNS 56

8. Change in HR in response to rFNS alone after propranolol administration measured at or 5 sec after peak MAP . . 58

9. Change in HR per unit change in MAP in response to PE infusion alone or in combination with rFNS after propranolol administration measured at or 5 sec after peak MAP 60

10. MAP and HR changes across time in a representative cat treated with PE alone (A), rFNS alone (B), and combination of PE and rFNS (C) 62

vi

11. Coronal section of cerebellum and brainstem in a representative cat from Group I in Part II 65

12. Linear regression curves for change in heart rate as a function of change in mean arterial pressure (MAP) during the fall in MAP after the administration of nitroprusside (NP) in Groups I-III 70

13. Changes in mean arterial pressure (MAP) across time showing response to nitroprusside (NP) infusion in a representative cat before and after bilateral rFNL 73

14. Change in HR per unit change in MAP in response to phenylephrine infusion measured at the same increased MAP (+30 mmHg) level before and after bilateral rFNL 82

vii

LIST OF ABBREVIATIONS

AVP: arginine vasopressin

BF: blood flow

C,: first cervical vertebra

Cj* second cervical vertebra

Co: third cervical vertebra

Cg: eighth cervical vertebra

CBF: cerebral blood flow

CNS: central nervous system

CSN: carotid sinus nerve

dl-hom: dextrolevo-homocysteate

FN: fastigial nucleus 3

H: tritiated hydrogen

HR: heart rate

HRP: horseradish peroxidase

IML: intermediolateral

lOD: dorsal accessory nucleus of the inferior olive

lOMC: medial accessory inferior olive, caudal division

lOMR: medial accessory inferior olive, rostral division

IVN: inferior vestibular nucleus

KA: Kainic acid

1-asp: levo-aspartate

viii

1-glu: levo-glutamate

LRN: lateral reticular nucleus

LVN: lateral vestibular nucleus

MAP: mean arterial pressure

MVN: medial vestibular nucleus

NMDA: N-methyl-dl-aspartate

NP: nitroprusside

NTS: nucleus of tractus solitarius

p: probability

PH: (nucleus) prepositus hypoglossus

PE: phenylephrine

PPN: propranolol

PRN: paramedian reticular nucleus

R: resistance

rFN: rostromedial fastigial nucleus

rFNL: lesions of rostromedial fastigial nucleus

rFNS: stimulation of rostromedial fastigial nucleus

rFNS2r: rFNS at 25 yA

rFNScQt rFNS at 50 yA

rFNS,QQ: rFNS at 100 yA

T..: first thoracic vertebra

V/: fourth ventricle 4

IX

CHAPTER I

INTRODUCTION

Statement of Purpose

Work by previous investigators has shown that electrical

stimulation of the cerebellar, rostromedial fastigial nucleus (rFN)

activates several pressor systems including the sympathetic nervous

system. Furthermore, bilateral lesions of rFN impair recovery of

mean arterial pressure (MAP) from several forms of hypotension, each

involving activation of more than one afferent pathway. The

objective of this dissertation research was to examine the effects of

electrical stimulation or lesions of the rFN on some autonomic

functions of the cardiovascular system in the cat. The study was

conducted in two parts. In the first part, experiments were designed

to determine whether rFN stimulation inhibits parasympathetic

activation induced by elevations of arterial blood pressure. In the

second part, lesions of the rFN (rFNL) were performed to investigate

the effect of bilateral rFNL on 1) sympathetic cardioacceleratory and

vasoconstrictor responses to transient, isovolemic hypotension

mediated primarily by arterial baroreceptors, and 2) baroreceptor

sensitivity on both the ascending and descending limbs of the

sensitivity curve.

2

Anatomy of the Cerebellar Fastigial Nucleus

The mammalian cerebellum is composed of an outer mantle of gray

matter, the cerebellar cortex, internal white matter, and four pairs

of deep cerebellar nuclei arranged on either side of the midline

(Carpenter and Sutin, 1983). According to Larsell and Jansen (1972),

the deep nuclei of the human cerebellum were designated the nucleus

fastigii, nucleus globosus, nucleus emboliformis, and nucleus

dentatus by Stilling in 1864-1867. The four deep cerebellar nuclei

in other mammals were described in 1899 by Weidenreich, who called

them the nucleus medius, nucleus lateralis posterior, nucleus

lateralis anterior, and nucleus lateralis. These were believed to

correspond to the human fastigial, globose, emboliform, and dentate

nuclei. Brunner reported in 1919 that the anterior and posterior

lateral nuclei were a single intermediate mass, which he called the

nucleus interpositus. In 1934, Ogawa reconsidered the nucleus

interpositus, proposing that it comprised of two separate nuclei: the

nucleus interpositus anterior and nucleus interpositus posterior.

This division was substantiated histologically in the cat by Snider

in 1940 and Flood and Jansen in 1961.

The fastigial nucleus (FN), the most medial of the deep

cerebellar nuclei, lies near the midline in the roof of the fourth

ventricle and is second in size to the dentate nucleus (Carpenter and

Sutin, 1983; Ghez and Fahn, 1981) (Figure 1). The FN can be divided

roughly into rostral and caudal portions on the basis of the cell

sizes, with large cells predominating in the rostral FN and small

cells in the caudal portion (Jansen and Jansen, 1955; Voogd, 1964).

Red nucleus

Midbrain

Pons

Central lobule Culmen

Linguia

Superior medullary velum

Medulla oblongata

Primary fissure

Declive

Horizontal fissure

Tuber vermis

Prepyramidal fissure

Pyramid

Postpyramidal fissure

5

The FN, as well as other deep cerebellar nuclei, receives the major

afferent fibers from Purkinje cells in the cerebellar cortex. On the

basis of the cerebellar cortical projections to the deep nuclei, the

cerebellar cortex has been divided into three rostrocaudal

longitudinal zones (Figure 2): a) a medial or vermal zone projecting

to the fastigial nucleus, b) a paravermal zone projecting to the

interposed nuclei, and c) a lateral or hemispheric zone projecting to

the dentate nucleus (Eager, 1963; Jansen and Brodal, 1940). The

vermal fibers project ipsilaterally to the nearest region of FN; thus

the anterior vermis projects to rostral FN, and the posterior vermis

projects to the caudal portion (Courville and Diakiw, 1976; Ruggiero

et_al., 1977; Carpenter and Batton, 1982).

The FN receives collaterals from the spinocerebellar mossy

fibers (Matsushita and Ikeda, 1970; Matsushita and Ueyama, 1973).

Other afferent inputs include fibers arising from several nuclei in

the brainstem including the medial vestibular, inferior olivary,

paramedian reticular, lateral reticular, and perihypoglossal nuclei

(Carleton and Carpenter, 1983; Carpenter and Batton, 1982). In

summary, major afferent fibers to FN are of three origins: a) the

cerebellar vermis, b) the spinal cord, and c) the brainstem.

Efferently, the FN projects to other parts of the central

nervous system (CNS) primarily through the contralateral uncinate

fasciculus and the ipsilateral restiform body (inferior cerebellar

peduncle) (Batton et al., 1977). Efferent fastigial pathways include

fibers to the nucleus of tractus solitarius (NTS), fastigiovestibular

fibers, fastigioreticular fibers, fibers to perihypoglossal nuclei,

To interposHus

To dentate

To fastigial

Vermis I Hemisphere

Intermediate part

Lateral part

8

fastigiopontine fibers, fastigiospinal projections, and ascending

fastigial efferent projections (Andrezik et al, 1984; Carpenter and

Batton, 1982; Ross et al., 1981). The afferent and efferent

fastigial pathways are discussed in Chapter IV.

Historical Development of Cerebellar and Fastigial Physiology

According to Dow and Moruzzi (1958), the history of cerebellar

physiology began in the seventeenth century when Du Verny reported

that pigeons with the cerebrum and cerebellum extirpated could still

be kept alive. Early investigations after Du Verny's report were

based primarily on ablation of cerebellum in birds and some mammals.

The modern period of cerebellar physiology began with Luciani, who

was the first to perform chronic ablation experiments on mammals in

the late nineteenth century. Thereafter, three methods have been

developed for the research of cerebellar physiology; they are

ablation, stimulation, and electrophysiological recording from the

cerebellum and other related sites in the CNS. Through these

techniques, previous investigators have found that the cerebellum is

involved in regulating the somatic motor, autonomic, and other

nonsomatic systems.

Cerebellar and Fastigial Physiology in the Somatic Motor System

The somatic functions of the cerebellum could be divided into

three categories: 1) postural tonus, 2) reflex phasic contractions,

and 3) voluntary movements. Electrical ablation was used in early

studies to demonstrate the cerebellar influence on postural tonus.

According to Dow and Moruzzi (1958), Luciani found in his classic

work in 1891 that unilateral cerebellectomy resulted in ipsilateral

extensor atonia in the dog and the cat. Yet cerebellectomy did not

abolish decerebrate rigidity: in fact, the latter was strengthened by

anterior lobe topectomy, as shown by Bremer in 1922, or total

cerebellectomy, as reported by Pollock and Davis in 1927. After

cerebellectomy, augmentation was noted in tendon reflexes by Luciani

in 1894 and Lewandowski in 1903; in magnet reaction by Rademark in

1931, and in labyrinthine reflexes by Pollock and Davis in 1927,

indicating that the cerebellum inhibits these reflexes. The atonia

Luciani described was observed in more recent experiments on

fastigial ablation by Batini and Pompeiano in 1955 and 1957:

ipsilateral extensor atonia was elicited by ablation of the rostral

FN and contralateral atonia by ablation of the caudal FN. Recently,

chemical ablation techniques have been developed, and, as reported by

Imperato et al. (1984), unilateral lesions of fastigial neurons with

kainate in the rat resulted in ipsilateral limb extensor atonia and

contralateral limb extensor hypertonus and abduction. Bilateral

chemical lesions of FN resulted in bilateral hyperextension and

abduction of the limbs. These results indicate that the cerebellum

and the FN exert a crossed inhibitory and an uncrossed excitatory

influence on limb postural tonus.

The technique of stimulating the cerebellum was used first in

the late nineteenth century, according to Dow and Moruzzi (1958).

10

In 1897, electrical stimulation of the anterior cerebellar cortex was

shown by Loewenthal and Horsley and by Sherrington to inhibit

decerebrate rigidity. Stimulation of the anterior vermis and the

rostral FN was noted by Moruzzi and Pompeiano in 1954 and 1956 to

result in ipsilateral inhibition of decerebrate rigidity.

Stimulation of the cerebellar cortex and FN can elicit various

responses in multiple systems as discussed in the next section.

Cerebellar electrophysiology began with the early attempts by

Beck and Bikeles in 1912 and Camis in 1919 to record bioelectrical

potentials from the cerebellar or related structures using a string

galvanometer. Modern electrophysiological studies began after Adrian

(1935) reported his recording of field potentials representing

cerebellar cortical activity during local stimulation. Unit activity

of the fastigial neurons has been recorded during stimulation of

cutaneous mechanoreceptors (Eccles et al., 1971, 1974) and afferent

nerves (Batini et al., 1983) in the cat and voluntary movement in

primates (Bava et al., 1983). Recording of field potentials during

fastigial stimulation has shown evidence of frontal cortical

response, relayed at the ventromedial and the medial areas of the

ventrolateral nuclei of the thalamus in the anesthetized cat

(Nakamura and Matsuda, 1983; Kyuhou and Kawaguchi, 1985).

Cerebellar and Fastigial Physiology Related to Autonomic and Other Nonsomatic Systems

According to Dow and Moruzzi (1958) and Wiggers (1943a), the

first observation of cerebellar involvement in nonsomatic functions

11

was made in 1858 by Claude Bernard, who reported that glycosuria

could be induced by cerebellar punctures in animals whose brainstems

were intact. Thereafter, a number of reports regarding the influence

of cerebellar stimulation or lesions on various vegetative functions

were published by several investigators. These early findings

included changes in blood sugar, body temperature, basal metabolism,

pupil diameter and movement of the nictating membrane, intestinal

motility, and bladder functions. The area of the cerebellum related

to blood sugar regulation was found by Wiggers (1943c) to be

localized in the uvula. Changes in the heart rate (HR), blood

pressure and spontaneous breathing after electrical and mechanical

stimulation of the cerebellar vermis were reported by Eckhard in

1872. Morruzi (1940) found that the vasopressor and respiratory

responses induced by carotid occlusion or intracarotid injection of

potassium cyanide were inhibited by faradic stimulation of the

anterior vermis of the cerebellum. Wiggers (1943b) reported

cardiovascular responses with stimulation of the anterior cerebellar

cortex. Years later, Hoffer et al. (1965, 1966) reconfirmed the

influence of the middle zone of the cerebellar cortex on

cardiovascular function. They observed a vasoconstriction of the

renal and vasodilatation of the skeletal-muscle vascular beds on

stimulation of this area of the cerebellum.

Stimulation of the cerebellar fastigial nucleus was noted first

by Zanchetti and Zoccolini (1954) to elicit cardiopulmonary

responses. By stimulating multiple sites in the cerebellum, these

investigators discovered that stimulation of the FN in decorticate

12

cats could elicit sham outbursts of rage. During the sham rage,

elevation of blood pressure and increases in respiratory frequency

were noted. The sensitive sites of the FN were located in the

rostral and central portions of the fastigial nucleus. The authors

hypothesized that these responses evoked by stimulating the rostral

FN in the decerebrate animals were dependent on the intact

hypothalamus. In 1969, both Miura and Reis (1969a) and Achari and

Downman demonstrated increases in arterial blood pressure and HR,

independent of sham outbursts of rage, with electrical stimulation of

the FN in anesthetized or decerebrate cats. Both groups reported

that the sites responsible for this pressor response were restricted

to the ventromedial border of the rostral FN, or, rostromedial FN

(rFN).

Subsequent studies have disclosed multiple influences of the rFN

area on autonomic function in the cardiovascular and other systems.

Generally, electrical stimulation of the rFN elicits autonomic

responses, that is, excitation of the sympathetic (Achari and

Downman, 1970; Doha and Reis, 1972b) and apparent suppression of the

parasympathetic (Lisander and Martner, 1971; Martner, 1975b) nervous

systems. In anesthetized animals, autonomic responses to rFN

stimulation include 1) a circulatory pressor response (Achari and

Downman, 1969; Miura and Reis, 1969), 2) inhibition of baroreflexes

(Achari and Downman, 1970; Hockman et al., 1970; Lisander and

Martner, 1971; Miura and Reis, 1971), 3) dilation of pupils and

retraction of nictating membrane (Achari and Downman, 1970), 4)

excitation or inhibition of the gastrointestinal motility (Lisander

13

and Martner, 1975b; 1975c; Martner, 1975a), and 5) inhibition of

defecation and micturition reflexes (Martner, 1975b). In

unanesthetized and chronically instrumented cats, electrical

stimulation of rFN could elicit marked changes in behaviors,

including grooming, drinking, feeding, and attack (Reis et al.,

1973). Reis et al. (1973) noted that a pressor response always

accompanied these behavioral changes, probably representing

anticipation of movement, a factor common to all of the behaviors

observed. Emotional excitement could be induced also by rFN

stimulation in chronically decerebrate cats; the responses included

running, lashing of the tail, and an increased respiratory rate

(Lisander and Martner, 1975a).

Cerebellar involvement in respiration was reported first by

Morruzi (1940): stimulation of the anterior cerebellar cortex

decreased respiration and inhibited cyanide-induced hyperpnea in

decerebrate cats. Stimulation of the rFN was found later to alter

respiration in either thalamic (Zanchetti and Zoccolini, 1954) or

anesthetized cats (Achari and Downman, 1970). Recently, Bassal and

Bianchi (1981) noted that stimulation of the FN produced excitation

of the phrenic and external intercostal nerves and inhibition of the

internal intercostal nerve. A recent report of Lutherer and Williams

(1986) showed quantitative changes in respiration evoked by rFN

stimulation. The respiratory changes, depending on frequency and

site of stimulation, included either a pure increase in respiratory

rate and mean inspiratory flow or biphasic responses characterized by

an initial apnea and a subsequent hyperpnea. Phase switching between

14

inspiration and expiration was observed with short-burst stimulation.

In a subsequent study, Williams et al. (1986) reported that

cerebellectomy or bilateral lesions of the rFN depressed respiration

by prolonging the interbreath interval and decreasing the ratio of

the duration of inspiration to the interbreath interval. These

results indicate that the cerebellum, especially the rFN area,

influences the control of respiration in a tonic fashion.

Although stimulation and lesioning studies have shown that the

rFN area is involved in various autonomic responses, it has not been

ascertained whether the neurons in or fibers of passage through the

rFN are responsible for these fastigial effects. Recently,

preliminary reports from Reis's laboratory (Chida et al., 1985; Chida

et al., 1986) showed that chemical stimulation of the rFN neurons

resulted in a depressor response, while electrical stimulation of the

rFN area could still elicit a pressor response after the local

neurons had been chemically lesioned. These results suggest that at

least the pressor response may involve fibers of passage originating

from some location other than the rFN. Electrophysiologically,

Lutherer et al. (1986) have documented changes in the firing rate in

cells within the rFN during cardiovascular and respiratory

challenges, but the efferent modality of these cells is unknown.

In summary, the somatic motor, autonomic, and other nonsomatic

systems have been found to be influenced by the cerebellar cortex and

the FN. While both rostral and caudal portions of FN are involved in

the somatic motor function, the sites involved in autonomic

regulation are restricted in the rostral portion of this nucleus.

15

Effects of Stimulation and Lesions of rFN on Cardiovascular Responses

Electrical stimulation of the rFN can elicit responses in the

heart and both the peripheral and cerebral vascular beds (Reis,

1984). This stimulation has been found to exert a stimulus-locked

pressor response in the cat (Miura and Reis, 1969a), dog (Dormer and

Stone, 1976), rat (Del Bo et al., 1983a), and rabbit (Nisimaru and

Kawaguchi, 1984). Miura and Reis (1970) termed the pressor response

observed in the cat the "fastigial pressor response." It is

characterized by a) increased systolic, diastolic, and mean arterial

pressures, b) decreased regional blood flow and increased resistance

in the peripheral vasculature (including the renal, mesenteric, and

skeletal-muscle vascular beds); c) increased total peripheral

resistance; d) increased blood flow in the common carotid artery, and

e) a small increase in HR and myocardial contractile force (Doha and

Reis, 1972a; 1972b). The patterned fastigial pressor response

approximates closely the cardiovascular responses elicited by

assumption of an upright posture (Gauer and Thron, 1965). There was

evidence indicating that the response was not elicited by spread of

the stimulus current to the brainstem (Miura and Reis, 1969). First,

the fastigial pressor response was different from the pressor

response evoked from stimulating the underlying brainstem regions, in

which the elevated blood pressure is associated with a bradycardia.

Second, a small electrolytic lesion at a positive locus in the FN

abolished the response. Third, the threshold to induce a fastigial

pressor response was low, averaging 50 A at a duration of 0.1 msec.

16

The optimal stimulus frequency was 30-80 Hz (cycles/sec). The

optimal localization of positive foci was restricted to the

ventromedial portion of the rostral third of FN and a limited portion

of white matter rostromedial to this particular FN region (Miura and

Reis, 1970).

Achari and Downman (1970) observed a similar pressor response

including increased blood pressure, peripheral vasoconstriction, and

increased HR during electrical stimulation of the medial and rostral

FN in anesthetized cats. They found that the fastigial blood

pressure and HR responses were abolished by sympathetic blocking

drugs. They concluded, therefore, that fastigial stimulation

augmented sympathetic discharges to the heart and the peripheral

vessels. Doha and Reis (1972b) showed that the cardiac and vascular

responses could be abolished by transection of the sympathetic

ganglia and nerves or by a- and 3-adrenergic blocking agents. They

drew a similar conclusion, namely, that the fastigial pressor

response was a result of activation of sympathetic preganglionic

neurons.

Acceleration of HR associated with blood pressure elevation

during rFN stimulation was seen more frequently in the dog than in

the cat (Dormer and Stone, 1976); however, the HR declined soon after

the blood pressure reached the peak and a baroreceptor-mediated

bradycardia usually followed. The difference between the two species

was suggested to be a predominantly vagal control of the HR in the

dog but not in the cat, but the fastigial pressor response in the dog

was considered to be a result also of widespread sympathetic

17

activation. Evidence was presented by Dormer et al. (1982) that the

fastigial sympathoexcitation in the dog is mediated, in a large part,

through the spinal sympathetic pathways. Clonidine is a central a^

agonist that acts in both the hypothalamus and the medulla; the net

result of administering clonidine is a diminished sympathetic outflow

from the CNS (Isaac, 1980). Intravenous infusion of clonidine

suppressed the MAP, HR, and left ventricular contractility responses

to rFN stimulation in both anesthetized and conscious dogs (Dormer

and Stone, 1978). Multiunit nerve activity recorded at the T„ or To

white ramus communicans was increased during rFN stimulation (Dormer

et al., 1982). This increment was abolished by bilateral lesions of

the dorsolateral funiculus (DLF) at the level of CQ. The DLF has

been shown in earlier investigations to be the site of the spinal

sympathetic pathways (Foreman and Wurster, 1973; Henry and Calaresu,

1974). In rabbits, the activity of the ipsilateral, renal

sympathetic nerve was increased with a concomitant rise in blood

pressure when the FN was stimulated (Nisimaru and Kawaguchi, 1984).

These responses could be elicited also by stimulating the caudomedial

portion of the FN in the rabbit. Thus far, this has been the only

exception to the topographical specificity of the rostral FN for the

pressor response. Lisander and Martner (1971) were the only group to

mention a contribution of parasympathetic withdrawal, in addition to

sympathoexcitation, to the fastigial pressor response. They noted

that rFN stimulation could increase the HR in cats even after spinal

transection at T,. Furthermore, when alprenolol, a 3-adrenergic

blockade, was given to cats with intact spinal cords, fastigial

18

stimulation increased the HR, an effect that was blocked by

pretreatment with atropine.

Cardiac arrhythmia evoked by stimulation of rFN has been

observed in anesthetized cats (Huang, 1977; Al Senawi and Downman,

1983) and dogs (Dormer and Stone, 1976). Huang (1977) found that

this arrhythmia in cats was abolished by atropine or vagotomy but

attenuated only slightly by propranolol. Moreover, the arrhythmia

remained after carotid sinus nerve section. He suggested that the

arrhythmic response does not originate entirely from a baroreflex and

that activation of both the sympathetic and parasympathetic nervous

system is involved in eliciting cardiac arrhythmia during FN

stimulation. This suggestion was not supported by a recent report by

Al Senawi and Downman (1983), who showed cardiac arrhythmia ranged

from sinus tachycardia to ectopic beats with FN stimulation in

anesthetized cats. The authors found that administration of

3-adrenergic blocking agents abolished the arrhythmic response during

stimulation, whereas bilateral vagotomy abolished only the

poststimulation ectopic beats. They concluded that the cardiac

arrhythmic responses are induced predominantly by sympathetic

activation resulting from fastigial stimulation. Fastigial

arrhythmia in the dog was explained to be an interaction of the

sympathetic acceleration and parasympathetic-mediated reflex

deceleration of HR (Dormer and Stone, 1976).

In addition to its influence on the autonomic nervous discharges

at the cardiac and vascular receptor sites, electrical stimulation of

the rFN elicits secretion of humoral factors. Fastigial stimulation

19

in anesthetized cats increased plasma renin activity secondary to an

increase in sympathetic renal activity; this FN-stimulated renin

secretion was not affected by a preset carotid sinus pressure (Koyama

et al., 1980). In rats, electrical stimulation of the rFN elicits a

typical fastigial pressor response (Del Bo et al., 1983a). In intact

rats or rats with combined chemosympathectomy and adrenalectomy,

fastigial stimulation elevates plasma arginine vasopressin (AVP).

The increased AVP was responsible for the late elevation of blood

pressure in rats with spinal cord transection. Because the release

of AVP is inhibited reflexly by elevated blood pressure during rFN

stimulation, the increment of AVP secretion was augmented after

combined sinoaortic denervation and vagotomy (Del Bo et al., 1984).

In another experiment, Del Bo et al. (1983b) demonstrated that both

plasma norepinephrine and epinephrine were elevated in rats during

stimulation of the rostral FN. Thus, stimulation of rFN elicits both

neural excitation and release of major vasoactive hormones. Because

the fastigial pressor response simulates cardiovascular responses to

positional changes (Gauer and Thron, 1965), the integrated

circulatory adjustments (neural and humoral) are consistent with a

proposed role for the cerebellum in governing the postural

cardiovascular adjustments, that is, the orthostatic reflexes (Del Bo

et al, 1983b).

Electrical stimulation of the rFN can elicit increases in

cerebral blood flow (CBF) (Reis, 1984). Doha and Reis (1972a, 1972b)

were first to note that rFN stimulation might increase CBF in the

cat, as reflected by decreased resistance and increased blood flow in

20

the common carotid artery. Increased CBF during rFN stimulation was

observed later in the monkey (McKee et al., 1976) and rabbit (Reis et

al., 1982). Recently, studies in Reis's laboratory showed that rFN

stimulation in the rat elicited vasodilation in the cerebral cortex

and selected regions of the telencephalon, diencephalon,

mesencephalon, lower brainstem, and white matter of corpus callosum

(Nakai et al., 1982). The rFN stimulation-induced cerebral

vasodilation persisted after transection of the spinal cord at C, or

the Vllth cranial nerves. It was impaired, however, by interruption

of the major extrathalamic projections to the cerebral cortex

originating in, or passing through, the basal forebrain (ladecola et

al., 1983). Where the regional CBF increases were the greatest

(particularly in the cerebral cortex), the local metabolism was

unchanged (Nakai et al., 1983). Reis (1984) concluded that cortical

vasodilation elicited by rFN stimulation is not coupled to local

metabolism, but mediated by intrinsic neuronal pathways depending on

the integrity of neurons originating in, or passing through, the

basal forebrain.

In summary, rFN stimulation elicits an autonomic nervous system-

mediated pressor response with additional secretion of pressor

hormones in the peripheral circulation and an intrinsic cerebral

vasodilation. The importance of the rFN area in regulating the

cardiovascular adjustment during daily activity such as exercise was

demonstrated by Dormer (1984) in conscious dogs. In dogs with

chronic bilateral lesions of the rFN (10-14 days of recovery),

increases in MAP and HR seen normally during an exercise-tolerance

21

test were attenuated significantly. This suggests that the neurons

in or projecting through the rFN excite the blood pressure and HR

responses during dynamic exercise. Some impairment in motor function

was noticed after rFN lesions in these animals, but the recovery was

rapid and the treadmill-exercise performance was unaffected if the

caudal FN was not lesioned. During exercise, the fastigial

contribution to increased CBF might be important for the increased

metabolic need in the brain.

Effects of rFN Stimulation on Baroreflexes and the Autonomic Output

Stimulation of the rFN has been shown by several authors to

inhibit baroreflexes and the mechanism was considered a predominant

activation of the sympathetic nervous system during rFN stimulation.

Achari and Downman (1970) were first to show that rFN stimulation

abolished reflex bradycardia induced by carotid sinus distension or

vagal afferent stimulation. It also inhibited chemoreflex

bradycardia induced by phenyl diguanide. Unlike the sham rage in

thalamic cats (Zanchetti and Zoccolini, 1954), this inhibitory effect

on baroreflex bradycardia was independent of the hypothalamus.

Although they found no evidence of alteration of vagal activity,

Achari and Downman stated that the existence of such an inhibition

could explain why fastigial stimulation could cause a marked rise of

blood pressure unaccompanied by any slowing of the HR even though the

sympathetic pathway was blocked by propranolol. In a subsequent

study performed in three conscious cats, Achari et al. (1973) showed

22

similar suppression of baroreflex cardiodeceleration by stimulating

the rFN. This inhibition persisted after pretreatment with

propranolol (2 mg/kg). This substantiated the concept that the

inhibition was caused not only by the onset of an equal and opposite

cardioacceleration of sympathetic origin but also by an inhibition of

parasympathetic output. Nevertheless, this possibility was not

discussed by the authors. Hockman et al. (1970) noted fastigial

inhibition of reflex bradycardia induced by carotid sinus nerve (CSN)

stimulation or aortic clamping in cats with the spinal cord

transected at C, (encephale isole preparation). The fastigial

inhibition of reflex bradycardia was abolished after midcollicular

decerebration, indicating the necessity of an intact forebrain for

this inhibition.

Lisander and Martner (1971) described a mutually inhibitory

intervention between the stimulated rFN and the distended carotid

sinus in the cat, with a stronger fastigial suppression of the

baroreflex action on the HR than on the vascular bed. They stated,

however, that the rFN region does not have a tonic influence on

either the resting cardiovascular activity or the cardiovascular

response to carotid baroreceptor unloading. There was no

experimental data shown in their report to substantiate this

statement. In their early studies, Miura and Reis (1969a; 1970)

noted that the fastigial pressor response was abolished by

destruction of the paramedian reticular nucleus (PRN), which seemed

to receive heavy projections from both the carotid and carotid

baroreceptor pathways. In a subsequent study, Mirua and Reis (1971)

23

showed that the carotid sinus depressor response, as well as the

fastigial pressor response could be abolished by bilateral lesions of

the PRN. In intact cats, however, the rFN and the CSN appeared to be

mutually inhibitory in a phasic fashion, because fastigial pressor

and CSN depressor responses could cancel each other if both sites

were stimulated simultaneously. Nevertheless, when the CSN and

aortic depressor nerve were sectioned bilaterally, the magnitude of

the fastigial pressor response was increased, suggesting that the

baroreceptors have a tonic inhibition on the fastigial pressor

response.

Stimulation of the rFN in the dog can suppress the depressor

response induced by nasal perfusion (diving reflex), a reflex

mediated through the trigeminal nerve (Dormer and Stone, 1980).

Huang et al. (1977) are the only group that have noted the importance

of the rFN area in maintaining normal baroreceptor sensitivity. They

showed that in cats and monkeys with acute bilateral rFN lesions, the

compensatory cardioacceleration in the early recovery phase after an

orthostatic tilt was impaired significantly. When the animals

underwent another tilt test six days after the lesion, the responses

had recovered almost completely. Hence, the authors hence

hypothesized that the impairment was compensated for by an augmented

baroreceptor unloading effect.

Although the fastigial influence on parasympathetic output in

the cardiovascular system has not been studied in detail, it has been

demonstrated clearly in other systems. In a series of studies,

Lisander and Martner (1975b, 1975c) and Martner (1975a, 1975b)

24

demonstrated the effects of fastigial stimulation on both the

sympathetic and parasympathetic activities of the gastrointestinal

system and urinary bladder in the cat. Through suppression of the

sympathetic tone in the intestines, rFN stimulation at the pressor

site increased motility in the ileum and colon (Martner, 1975a).

Subsequently, fastigial suppression of the laparotomy-elicited

intestinal inhibitory reflex was noted (Lisander and Martner, 1975b).

Gastric motility was found to be increased or decreased during rFN

stimulation (Lisander and Martner, 1975c). Fastigial suppression of

gastric motility was shown to be mediated by increased sympathetic

tone, and gastric excitation by increased parasympathetic tone. This

increase in gastric parasympatheic tone is different from the

parasympathetic activity in reflexes of the gastrointestinal system

as discussed below. With rFN stimulation, the increased colonic

motility exerted by mechanical rectal or afferent pelvic nerve

stimulation was abolished (Martner, 1975b). The reflex rectal

vasodilation during defecation and the urinary bladder contraction

elicited by distention of bladder with saline were inhibited by rFN

stimulation. The inhibition of both the defecation and micturition

reflexes during rFN stimulation was unaffected by either sympathetic

nerve sectioning or by adernergic blocking agents, but was eliminated

by pelvic nerve section. Thus, this fastigial inhibition results,

not from prevailing activation of sympathetic adrenergic fibers, but

from suppression of the parasympathetic mediation of these reflexes.

In summary, stimulation of rFN interferes with cardiovascular

effects of baroreflexes and other reflexes, for example, defecation

25

and micturition reflexes, which are mediated by the autonomic nervous

system. The rFN area influences these reflexes by altering the

output of both the sympathetic and parasympathetic components of the

autonomic nervous system.

Effects of rFN Lesions or Cerebellectomy on Cardiovascular Responses to

Hypotensive Challenges

The importance of the integrity of the rFN pressor area in blood

pressure recovery has been demonstrated in two types of studies.

Bilateral lesions of rFN or cerebellectomy impaired blood pressure

recovery from either a mild, transient hypotension induced by

orthostatic tilt (Doha and Reis, 1974; Huang et al., 1977; Koyama et.

al., 1981) or a severe, long-lasting hypotension induced by

hemorrhage (Lutherer et al., 1983a, 1983b) or endotoxin (Janssen et

al., 1981; Lutherer et al., 1983a).

According to Doha and Reis (1972a, 1974), the reflex blood

pressure response in anesthetized cats subjected to 30 or 60 head-

up tilt can be depicted schematically in three phases: 1) an early,

uncompensated phase corresponding to the initial fall in blood

pressure, 2) an early, compensated phase with recovery of blood

pressure, and 3) a late, compensated phase with blood pressure

sustained at or near the control level. There was an associated

reflex acceleration of HR during all three phases. After bilateral

lesions of the rFN, the blood pressure response to tilt was impaired.

The deficits included: 1) an augmentation of the initial fall in

26

blood pressure, 2) a delay in the onset of early, compensated

recovery, and 3) a failure during the late, compensatory phase of

blood pressure to return to control values. Bilateral extracranial

lesion of the vestibular nerves impaired the responses to tilt as did

bilateral rFN lesions. When the carotid sinus and the vagus nerves

were transected bilaterally, the resting blood pressure was elevated

but the recovery of blood pressure in response to tilt was abolished.

Superimposed fastigial lesions in the barodenervated cats resulted in

a greater initial fall in blood pressure in response to tilt. The

elevated resting blood pressure resulting from barodenervation was

lowered remarkably by subsequent administration of phentolamine. The

impaired blood pressure response to tilt after bilateral rFN lesions

was caused probably by an attenuation of vasoconstriction. Doha and

Reis (1974) noted that femoral vascular resistance measured at nadir

blood pressure during orthostatic tilt was reduced significantly.

They did not see a change, however, in the tilt-induced reflex

cardioacceleration with rFN lesions.

Similar decreases in blood pressure during orthostatic tilt were

observed by Huang et al. (1977) in cats and monkeys with acute

bilateral rFN lesions. In contrast to Doba and Reis (1974), they

noted a significant attenuation of reflex cardioacceleration during

the early recovery phase after acute rFN lesions in both species.

Because plasma renin activity was elevated during orthostatic tilt,

Koyama et al. (1981) concluded that the renin-angiotensin system also

was involved in mediating blood pressure changes in response to tilt.

Yet bilateral rFN lesions did not alter the renin secretion elicited

27

by orthostatic tilt. The increased renin secretion was abolished by

bilateral vagotomy regardless of the prefixed levels of the carotid

sinus pressure, with or without rFN lesions. In summary, during

orthostatic tilt, factors including the vestibular pathways, arterial

and cardiopulmonary receptors, pressor hormones, and the rostral FN

are involved in the cardiovascular response.

Janssen et al. (1981) showed that cerebellectomy impaired MAP

recovery from endotoxin-induced hypotension in the dog. Intravenous

bolus infusion of Escherichia Coli endotoxin in intact, anesthetized

dogs resulted in a hypotensive state that lasted for an observation

period of 3 hours. The hypotensive state comprised three phases:

1) an initial hypotensive phase reaching a maximum by 2 min, 2) a

recovery phase (50% of recovery) completed by approximately 30 min,

and 3) a maintenance phase from 60 min to the end of 3 hours. When

endotoxin was administered to dogs with the cerebellum removed, the

initial decrease in MAP in response to endotoxin was not affected;

however, both the recovery and the maintenance phases were impaired

severely. Pretreatment with captopril or spinal transection at C«

level resulted in similar impairment of MAP recovery as did

cerebellectomy. Lutherer et al. (1983a) later examined the effects

of bilateral rFN lesions on the recovery of MAP from endotoxin or

hemorrhagic shock. Bilateral lesions of the rFN (rFNL) or

cerebellectomy did not affect the loss of blood required to reduce

MAP to 50 mmHg; however, the recovery and maintenance phases in both

hemorrhagic and endotoxin shock models were impaired severely by

bilateral rFNL.

28

Renin-angiotensin and AVP participate in pressor response to

hypotension, and plasma levels of renin (Koyama et al., 1980) and AVP

(Del Bo et al., 1982) were found to increase during rFN stimulation.

The significance of the cerebellar involvement in renin and AVP

secretion was examined by Lutherer et al. (1983b) in a hemorrhage

study performed in intact and cerebellectomized dogs. Pretreatment

with captopril or AVP antagonist alone impaired recovery also and the

impairment was not greater then that resulting from cerebellectomy.

Combined treatment with cerebellectomy and AVP antagonist did not

produce a greater deficit than cerebellectomy alone; however,

superimposed infusion of captopril in cerebellectomized cats led to

an earlier death in all dogs tested. The animals that died did so

from cardiac arrest after a period of apnea. The results of the

above studies (Koyama et al., 1980; Del Bo et al., 1982; Lutherer et

al., 1983b) suggested that the cerebellum, especially the rostral FN,

is important in some activation of the renin-angiotensin system and

probably most of AVP secretion during severe hypotension.

In summary, the cerebellum, especially the rostral FN area, is

essential to normal cardiovascular responses to hypotensive

challenges including orthostatic tilt, hemorrhage, and infusion of

endotoxin. Multiple pressor factors in addition to arterial

baroreceptors are activated during these forms of hypotension. The

role of the rFN area in modulating cardiovascular responses purely to

impulses from arterial baroreceptors is yet to be determined.

29

Background for the Dissertation Research

Part I. Influence of rFN Stimulation on Cardiac Parasympathetic Activity

After the early reports of Achari and Downman (1970) and Doba

and Reis (1972b), it has been believed generally that the excitatory

effects of rFN stimulation on the cardiovascular system are elicited

by activation of the sympathetic nervous system. Because the

cardiovascular system, especially the heart, is innervated by both

sympathetic and parasympathetic nerves, one would speculate that both

components of the autonomic system are modified in response to

fastigial stimulation. Although fastigial suppression of

parasympathetically mediated reflexes (defecation and micturition)

has been demonstrated in other organs (Martner, 1975b), the

contribution of the parasympathetic mediation of the cardiovascular

responses has been overlooked.

Achari and Downman (1970) stated that during rFN stimulation

there was no change in vagal activity. Doba and Reis (1972b) did not

test the possibility of a vagal participation in the fastigial

pressure response. Although Lisander and Martner (1971) suggested

that the fastigial cardioacceleration was elicited both by an

increase in sympathetic discharge and a withdrawal of vagal tonic

inhibition, the evidence they presented was weak and indirect. In

their experimental design, fastigial cardioacceleration was sustained

in cats with spinal transection at T, or with 3-adrenergic blockade.

They showed that the persistent fastigial cardioacceleration in these

30

cats could be abolished by prior vagotomy or administration of

atropine. Nevertheless, it is difficult to prove further

parasympathetic withdrawal during fastigial stimulation if the

parasympathetic activity has been blocked by vagotomy or atropine.

Although Hockman et al (1970), in a largely neglected short

communication, showed persistent fastigial inhibition of reflex

cardiodeceleration in cats with spinal transection, they did not

conclude that fastigial stimulation can suppress parasympathetic

activation. Their study was by no means complete because the

fastigial effect was not tested at low (threshold) stimulus

intensities and the data were not analyzed statistically. Achari et

al. (1973) showed persistent fastigial suppression of baroreflex

cardiodeceleration in three conscious, propranolol-treated cats, but

did not address clearly the parasympathetic mediation of this effect.

Furthermore, the small size of the experimental group precluded

statistical analysis of data was not obtainable in their study.

In the first part of the present study, the experiment was

designed to confirm the concept that in addition to activating the

sympathetic drive, stimulation of the rFN area inhibits parasym

pathetic discharge to the heart. Fastigial stimulation at low

intensities (25, 50, and 100 yA) was performed in anesthetized cats

before and after pretrearaent with propranolol. The changes in HR and

MAP were recorded during both a control period of rFN stimulation

alone and a second period with concomitant phenylephrine infusion.

The effect of rFN stimulation on cardiac parasympathetic activation

induced by elevated MAP was studied qualitatively and quantitatively.

31

Part II. Effects of Bilateral rFN Lesions on Cardiovascular Responses to Transient Hypotension and on Baroreceptor Sensitivity

As reviewed above, the importance of the rFN pressor region in

normal cardiovascular responses has been demonstrated in two types of

hypotensive challenges. Bilateral lesions of rFN (rFNL) impair blood

pressure recovery after a mild, transient hypotension induced by

orthostatic tilt (Doba and Reis, 1974; Huang et al., 1977; Koyama et

al., 1981). Cerebellectomy or bilateral rFNL resulted in severe

impairment in MAP recovery during long-lasting hypotension induced by

hemorrhage or endotoxin (Janssen et al., 1981; Lutherer et al.,

1983a, 1983b). During orthostatic hypotension, the central nervous

system receives afferent information from vestibular receptors as

well as arterial baroreceptors, and transection of both vestibular

nerves impairs blood pressure recovery to the same degree as

bilateral lesions of rFN (Doba and Reis, 1974). Hypotension induced

by hemorrhage or administration of endotoxin involves actual or

effective loss of blood volume; therefore, low-pressure receptors are

activated also with resultant secretion of renin and vasopressin.

This study was designed to examine the effects of bilateral lesions

of rFN in a hypotensive model involving responses mediated primarily

by the arterial baroreceptors.

Transient hypotension was induced in anesthetized cats with

bolus infusion of sodium nitroprusside (NP) and the cardiovascular

responses were studied before and after bilateral rFNL. Changes in

HR, MAP, and femoral blood flow and resistance were compared between

values measured before and after bilateral rFN lesions. The effect

32

of NP is rapid in onset and short lived (Blaschke et al., 1980).

Because of the pharmacokinetics of NP, the arterial blood pressure of

subjects receiving NP by bolus infusion was shown to decrease

immediately and return to the control level in 4 min (Chen et al.,

1982). Although the specific objective in this study was to

determine the fastigial influence on arterial baroreceptor-mediated

autonomic activity in this particular hypotensive model, renin-

angiotensin involvement was examined also for the following two

reasons: first, it has been shown that secretion of renin was

increased at 30 min of prolonged, high dose infusion of NP in

different species (Francis et al., 1983; Knight et al., 1983; Miller

et al., 1977); second, rFN stimulation was shown to increase plasma

renin activity (Koyama et al., 1980). Thus, captopril was given to

block angiotensin activity in some sham-operated cats, and the

cardiovascular response to NP-induced hypotension was examined under

this blockade. In other sham-operated cats, PPN was administered

before infusion of NP to examine the involvement of both a- and

3-adrenergic systems in MAP and HR responses to this hypotensive

challenge.

In previous hypotensive studies, the influence of FN lesions on

baroreceptor sensitivity was not measured quantitatively. Huang e^

al. (1977) were the only group to show impaired acceleration of HR

during blood pressure recovery in acute FN-lesioned animals. Because

of the rapid fall and recovery of MAP after bolus infusion of NP, the

NP-induced hypotension is a perfect model for measuring the

baroreceptor sensitivity (Chen et al., 1982). Chen et al. (1982)

33

concluded that baroreceptor sensitivity was under the dual influences

of both the sympathetic and parasympathetic nervous systems. In the

present study, baroreceptor sensitivity was examined during the fall

of MAP before and after bilateral lesions of rFN; additional

experiments involving infusion of phenylephrine were performed to

examine the influence of bilateral rFN lesions on the ascending limb

of the sensitivity curve. In previous reports, a tonic influence of

the rFN pressor area on the cardiovascular system was either rejected

(Lisander and Martner, 1971) or not mentioned. In this study, a

possible tonic influence of the rFN area on MAP and HR as well as

baroreceptor sensitivity was examined in detail.

CHAPTER II

MATERIALS AND METHODS

General Preparation of the Cats

The study was conducted in two parts. Part I and Part II.

Experiments were performed in 54 mongrel male or female cats,

weighing from 2.5 to 3.5 kg. Among the 54 cats, 12 were used in Part

I and 42 in Part II. The animals were fasted 12 hours before the

experiment. All cats were anesthetized during the experimental

period. Anesthesia was induced by intramuscular injection of

ketamine hydrochloride (20 mg/kg) and maintained by intravenous

injection of a mixture of a-chloralose (20 mg/kg) and urethane (350

mg/kg). Catheters containing heparinized normal saline were

introduced into 1) the abdominal aorta through the right femoral

artery for blood pressure monitoring and withdrawal of blood samples

for arterial blood gas analysis and 2) the inferior vena cava through

the right femoral vein for infusion of drugs and anesthetic. The

cats were placed in a Kopf stereotaxic apparatus, and, after removal

of overlying soft tissue, a small hole was made in the skull rostral

to the occipital protuberance. Supplemental anesthetic was

administered according to a schedule determined previously in

nonparalyzed animals. All cats were paralyzed with gallamine

triethiodide (5 mg/Kg, iv.) and ventilated artificially with room

34

35

air. End-tidal CO^j measured by an infrared gas analyzer (Beckman

LB2), was maintained at 3-4%. Arterial blood gases were analyzed

(Radiometer Blood Micro System and Digital Acid-Base Analyzer) at

one-hour intervals. Throughout the experiments arterial pH was

maintained in a range of 7.36 to 7.44; PaC02, ^^ ^^ ^° ^^ mmHg; and

PaO^, at 75 to 80 imnHg by adjusting the frequency and tidal volume of

the ventilation. Rectal temperature was maintained between 36.5 C

and 37.5 C by a thermostatically regulated, infrared lamp.

Blood Pressure, Heart Rate, and Blood Flow Monitoring

Lead I ECG and mean arterial pressure (MAP) were recorded on a

Narco Biosystems Physiograph recorder. The beat-to-beat HR was

determined from logic pulses generated by an amplitude analyzer that

discriminated the R waves in an ECG waveform. These pulses were

routed to an Apple lie computer. The software program detected the

incoming pulses and timed the intervals between them, using an on

board clock. For each pulse acquired, an A/D board in the computer

sampled the MAP signal from the Narco Physiograph recorder. The R-R

intervals were converted inversely into HR which was expressed as

beats per minute.

Blood flow (BF) was measured in the left femoral artery (SWF-4

flowmeter, Zepeda) in some cats. At the end of the experiments, the

flowmeter was calibrated in each cat in situ with the cat's own

blood. The vascular resistance (R) of the femoral artery was

calculated using the conventional formula: R = MAP/BF.

36

Administration of Drugs

All drugs were given intravenously with a rapid, bolus infusion.

Elevation of MAP was induced with phenylephrine (PE, 20 yg/kg).

Atropine (1 mg/kg) was given to block cardiac muscarinic receptors

for cholinergic output. Hypotension was induced by sodium nitroprus

side (NP, 10 yg/kg) freshly dissolved in 5% dextrose in water and

protected from light by aluminum foil (Arnold et al., 1984). All

other agents were freshly dissolved in saline. Captopril (0.2 mg/kg)

was given to block formation of angiotensin II, and effectiveness of

blockade was confirmed by lack of a pressor response to angiotensin I

(0.5 yg/kg). Cardiac 3-adrenergic receptors were blocked by

propranolol (PPN, 1 mg/kg), and adequate blockade was validated with

an isoproterenol challenge (1 yg/kg) (Shanks, 1966; Sharma, 1967).

In preliminary studies, blockade at the doses designated was

effective for at least 30 min.

Stimulation and Lesion

A stainless steel, concentric, bipolar electrode (Rhodes Medical

Instruments, NE-100) was introduced at a 45 angle into the

cerebellum, approximately 1 mm lateral to the midline. The electrode

was advanced to just above the FN according to Berman's coordinates

(Berman, 1968). It was then lowered in 0.2-mm steps until an

optimal, stimulus-locked increase in blood pressure was obtained in

response to constant current stimulation of 25 to 50 yA at 50 Hz and

0.1-msec pulse duration for 10 sec (Grass SD9 and WPI model 305). In

37

Part I, a small lesion with DC current (200 yA, 20 sec) was made at

the stimulated sites at the end of experiment for histological

verification of these sites. In Part II, bilateral, complete lesions

of rFN were made with DC current (30 volt, 60 sec) as part of the

experimental protocol in some groups.

Histology

At the end of the experiment, the still-anesthetized animal was

killed by intravenous injection of saturated potassium chloride while

still anesthetized. The cerebellum and the brainstem were removed

and fixed in 10% formaldehyde solution. In Part I, the formaldehyde

solution was prepared to contain 2% potassium ferrocyanide for better

identification of the small lesion sites. The fixed tissue specimens

were then sectioned into 50 ym slices with a freezing microtome. The

slices were stained with cresyl violet for the determination of the

sites and sizes of the lesions.

In Part I, the tissue was sectioned sagitally and the active

sites showing optimal response to fastigial stimulation were

identified. In Part II, coronal sections of the tissue specimens

were made. Cats were designated as having bilateral rFNL if

histological sections showed that 50-100% of the rFN was ablated on

both sides. This criterion was met in 12 of the 18 cats receiving

lesions. Lesions in the other 6 cats failed to meet the above

criterion, that is, lesions of less than 50% of the rFN on both

sides. These lesions were designated as incomplete rFNL.

38

Protocol and Statistical Analysis

Part I.

Protocol. The 12 cats used in this part were separated into

three groups. Groups A, B, and C (Table 1). Group A was designed to

examine HR and MAP responses to rFN stimulation (rFNS) alone,

infusion of phenylephrine (PE) alone, and combined rFNS and infusion

of PE, with or without 3-adrenergic blockade with PPN. Group B was

designed to examine the influence of atropine on the effects of PE.

Animals in Group C were first treated with PPN; the effects of rFNS

alone and PE infusion alone were then examined before and after

atropine administration.

Three procedures were performed in Group A (n = 6) before

administraton of PPN. In procedure 1, rFNS alone was done at 25, 50,

and 100 PA (0.1 msec, 50 Hz) in random order. PE (20 yg/kg) was then

administered alone as procedure 2. In procedure 3, PE (20 yg/kg)

infusion was combined with concomitant rFNS at 25, 50, and 100 yA

(0.1 msec, 50 Hz) in random order. After administration of PPN (1

mg/kg), the same protocol was repeated. With rFNS alone, stimulation

was stopped each time at peak MAP for two reasons. First, according

to preliminary studies, the maximal effect of rFN stimulation on HR

response occurred at peak MAP; a special interest in this part of the

study was to measure the maximal effects of rFN stimulation on both

MAP and HR responses. Second, it was noted in preliminary studies

and also by other investigators (Dormer and Stone, 1976; Lutherer and

Williams, 1986) that both MAP and HR levels started to decline after

peak MAP was reached, even though the stimulation was continued.

39

Table 1

Protocol in Part I

Group A (n = 6)

Before PPN

Procedure 1: rFNS alone; rFNS^^, rFNS.^, rFNS,^^ (random order) 25 50' 100

Procedure 2: PE alone

Procedure 3: PE + rFNS; PE + rFNS^,, PE + rFNS,^, PE + rFNS^^^ (random order) ^^ ^^ ^^°

After PPN

Repeat the above procedures

Group B (n = 3)

Before Atropine

After Atropine

PE alone

PE alone

Group C (n = 3)

After PPN

Before Atropine

After Atropine

PE alone; rFNS,p p alone (random order)

PE alone; rFNS, . alone (random order)

PPN, propranolol; PE, phenylephrine. rFNS, stimulation of rostromedial fastigial nucleus at 0.1 msec, 50 Hz; subscript numbers: stimulus intensity (yA). n, number of animals.

40

One objective in this part was to measure the maximal HR response as

a function of elevated MAP. Results of preliminary studies showed

that the maximal HR change occurred at peak MAP level induced by PE

alone. To test the influence of concomitant rFN stimulation on the

maximal HR response to elevated MAP, the stimulation was continued

until peak MAP was reached. The peak of MAP elevation was identified

when MAP started to plateau. According to the trials in preliminary

studies, the onset for the infused PE to circulate was approximately

2 sec; therefore, the concomitant rFN stimulation was started 2 sec

after PE infusion in each cat.

In Group B (n = 3), infusion of PE alone was given before and

after pretreatment with atropine. In Group C (n = 3), the cats were

pretreated with PPN, after which rFNS at 100 yA or infusions of PE

were performed before and after superimposed pretreatment with

atropine. Between steps, adequate time was allowed for HR and MAP to

recover to the resting levels in all animals.

Statistical Analysis. A two-tailed Student's t-test was used

for single comparison of resting HR and MAP before and after

administration of PPN. For multiple comparisons among groups, a two-

way analysis of variance (ANOVA) followed by Newman-Kuels test was

used. A p-value of < 0.05 was considered significant.

Part II.

Protocol. In this part, cats (n = 42) were separated into six

groups according to test agents and treatments (Table 2). The test

Table 2

Protocol in Part II

41

Group n time-1 Treatment time-2

I

I I

I I I

IV

V

VI

12

6

6

6

6

6

NP-1

NP-1

NP-1

NP-1

NP-1

PE-1

Bilateral rFNL

Incomplete rFNL

Sham

Sham + Captopril

Sham + Propranolol

Bilateral rFNL

NP-2

NP-2

NP-2

NP-2

NP-2

PE-2

rFNL, lesions of the rostromedial fastigial nucleus; NP, nitroprusside; PE, propranolol, n, number of animals. See text for other explanations.

42

agents (NP or PE) were administered twice in each cat. At the

beginning of the experiment, bilateral stimulation of rFN was

performed in each cat. After a 30 min recovery period, the first

infusion of the test agent (NP-1 or PE-1) was given (time-1). After

another 30 min, lesions of the rFN were performed in cats to be

assigned after histological evaluation to Groups I and VI (bilateral

rFNL) and Group II (incomplete rFNL). Stimulation of rFN as a sham

lesion was performed in all other groups. Group III served as time-

matched control to ensure that time alone did not alter the response

to the second infusion. One hour later (time-2), the test agent (NP-

2 or PE-2) was infused a second time. In Groups IV and V, captopril

and PPN, respectively, was infused 5 min before NP-2. Preliminary

studies showed that blockade was complete within 5 min, and, in the

experimental series, challenge at this time was not repeated. The

challenge was administered, however, after recovery from changes

induced by the test agents in order to insure that the blockade was

still in effect.

Statistical Analysis. For single comparisons of values between

NP-1 and NP-2 or between PE-1 and PE-2 in the same cats within each

group, a paired t-test was used. Linear regression was used to

compare the change in HR as a function of change in MAP between NP-1

and NP-2 in Groups I-III. A p-value of < 0.05 was considered

significant.

CHAPTER III

RESULTS

Part I. Influence of rFN Stimulation on Cardiac Parasympathetic Activity

Histology

The active sites in the rFN showing optimal pressor response to

electrical stimulation are demonstrated in a camera lucida drawing of

sagittal cerebellum and brainstem sections approximately 0.6-1.2 mm

from the midline (Figure 3).

Effects of Propranolol on MAP and HR Responses to rFNS

The effects of PPN on resting MAP and HR values measured before

treatments in Group A are presented in Table 3. The maximal changes

in MAP and HR and change in HR per unit change of MAP in response to

treatments with rFN stimulation (rFNS) alone, PE infusion alone, and

combined rFNS and infusion of PE, before and after PPN adminis

tration, are shown also in Table 3. Resting HR, measured immediately

before each treatment, was decreased by PPN; the total average value

was reduced significantly, from 187 j^ 3 to 144 +_ 2 beats/min (p <

0.001). The influence of PPN on resting MAP was not significant (132

+ 2 v£. 129 ± 2). Electrical stimulation of rFN at 25, 50, and

43

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48

100 yA elicited increases in both MAP and HR, before and after PPN.

The increasing MAP reached the peak within in 20 sec and declined as

soon as the stimulation was stopped; the increasing HR reached its

highest point also at peak MAP and then declined when stimulation was

stopped (Figure 4). After PPN, the magnitudes of MAP and HR

responses to rFNS were reduced, but the patterns of these responses

across time remained similar (Figure 5). The maximal increase in MAP

and the associated increase in HR, which was usually also the maximal

increase in HR, were reduced but not abolished by PPN at all stimulus

intensities tested (Figure 6). Either before or after PPN, the

maximal change in MAP increased as the stimulus intensity increased,

and the change evoked at 100 PA was reduced significantly by PPN

(Figure 6, upper panel). The increment in HR was reduced by PPN at

all intensities tested (Figure 6, lower panel). The change in HR was

amplified also by increasing stimulus intensity and the difference

between that evoked by 25 yA and 100 yA was significant either before

or after infusion of PPN.

Inhibition of rFNS on PE-induced Reflex Cardiodeceleration Before and After Administration of 3-adrenergic Blockade

Bolus infusion of PE exerted an immediate elevation in MAP of

50-90 mmHg in 15 sec, with or without PPN. A baroreflex cardio

deceleration was induced by the elevations in MAP. The reflex

cardiodeceleration measured at the time of maximal change in MAP was

not altered by PPN (-0.48 + 0.11 v^. -0.47 ± 0.08 beats/min/mmHg).

50

rFNS.nnBefore PPN '100

MAP

250 -

I Q. <

200 -

150 -

1

• 9 0 -I

V60 -

X E E

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0 -

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— I — 20 30

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0 -

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—I 30

TIME (sec) TIME (sec)

52

rFNSioo After PPN

MAP

250 -

^ 200

<

150 -

•90 n

• 6 0 -

o> X E E

i ^30

0 -

t HR

• 3 0 -I

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c "E

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cr X

200 -

150

• 20 - I

c E

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CO X

0 -

r 10

- T -20

I 30

TIME (sec)

54

100 T

^ 80 ••

X E

g 60 -

< 40 •• 20 -

I I Before PPN

After PPN

c E

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30 T

25 ••

20 •

15 •

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rFNSjs rFNS 50 rFNSioo

55

The reflexly decreased HR returned to the resting level within 3 min

after infusion of PE.

During concomitant rFNS and infusion of PE, the maximal increase

in MAP (70-110 mmHg) was greater than that exerted by either

treatment alone but less than the arithmetic sum of both. The

maximal reflex cardiodeceleration induced by infused PE was

suppressed significantly, however, by concurrent rFNS. This

fastigial suppression of reflex cardiodeceleration was not attenuated

when the cardiac 3-adrenergic sympathetic receptors were blocked by

PPN. As shown in Figure 7, the PE-induced reflex cardiodeceleration

was suppressed by concurrent rFN stimulation at 25, 50, and 100 yA.

The fastigial suppression was accentuated by increasing the stimulus

intensity. At 100 yA, the deceleration reflex was inhibited totally

and the change in HR per unit change in MAP became positive.

Pretreatment with PPN did not alter this fastigial suppressive effect

on reflex cardiodeceleration at any stimulus intensity tested.

Under PPN blockade, the acceleration of HR induced by rFNS alone

was no longer evident at 5 sec after the stimulation was stopped at

peak MAP. As shown in Figure 8, the change in HR in response to rFNS

alone became negative at this time regardless of the intensity of

stimulus. Reflex cardiodeceleration induced by PE alone remained

unchanged at 5 sec after peak MAP (Figure 9). The PE-induced reflex

cardiodeceleration suppressed by rFNS reappeared at 5 sec after the

rFNS was stopped at peak MAP (Figure 10).

In Figure 10, the data from a representative cat demonstrate the

changes in MAP and HR across time in response to PE infusion alone.

57

I I Before PPN

After PPN

X E E

c E

(0 ^•^ (0 o

Q. <

<

X

0.2 ^

0.0

- 0 . 2 ••

-0.4 ••

•0.6 i

PE alone

PE + rFNS

ZZLZA

25

PE + rFNS

7

50

PE + rFNSioo

59

r: ^ : At Peak MAP

531: 5 sec after Peak MAP

15T

(0 "S o

X <

1 0 "

5--

5--

10--

15-L

rFNS 25 rFNSso rFNSioo

61

^ : At Peak MAP

5 sec after Peak MAP

.2T

O) z E E

c E

"5 a> S -.4 + Q. <

-.2 ••

<

OC X <

.6 -•

-.8-I-

PE alone

PE + rFNS 25

PE + rFNS 50

PE + rFNS 100

63

MEAN ARTERIAL PRESSURE

250 -,

A; PE alone

180 -I

*? 160 -

to « 140 J3

CL X 120

f

HEART RATE

> 1 1 1 1 1 1 I I I 1 I

2 5 0

B: rFNS,oo ^ilone

180 n

cr X 120 -

T r T r

250 n

C: PE+rFNSioo

1 8 0 -

—r-10 2 0 3 0 4 0

TIME (sec)

—r— 50

—I 60

—T-10 30 20

TIME (sec)

4 0 —r-50

—I 60

64

rFNS at 100 yA alone, and combined treatment with the two. The HR

was elevated from the resting level during rFNS either alone or in

combination with infusion of PE. Immediately after the stimulation

was stopped in both conditions, HR declined and reached the bottom

level in approximately 5 sec.

Influence of Atropine on PE-induced Reflex Cardiodeceleration

The influence of atropine on PE-induced cardiodeceleration was

examined in Group B. PE infusion-induced reflex cardiodeceleration

(-0.45 to -0.51 beats/min/mmHg) was abolished by pretreatment with

atropine in all 3 cats. There was an increase of 15-20 beats/min in

resting HR after administration of atropine. In Group C, cats were

pretreated with PPN, and atropine increased the resting HR for 10-18

beats/min. Reflex cardiodeceleration (-0.43 to -0.52 beats/min/mmHg)

induced by infusion of PE was also abolished by atropine pretreatment

in all 3 cats. Acceleration of HR (+0.10 to + 0.15 beats/min/nmiHg)

evoked by rFNS at 100 yA was reduced to zero in all 3 cats.

Part II. Effects of Bilateral rFN Lesions on "Baroreceptor Sensitivity and Cardiovascular

Responses to Transient Hypotension

Histology

Lesions of rFN fulfilling the criterion of bilateral rFNL in a

typical cat in Group I are shown in the photograph of a coronal

section of the cerebellum and brainstem (Figure 11).

67

Effects of rFN Lesions on Resting MAP and HR

The values of resting MAP and HR at time-1 and time-2 in Groups

I-III are presented in Table 4. In Group I, the resting HR decreased

in each cat after bilateral FNL, and the difference between group

means was significant. The resting HR was not changed with

incomplete (Group II) or sham lesions of rFN (Group III). Lesions of

rFN did evoke a significant change in resting MAP.

Effects of rFN Lesions on Initial Decrease in MAP and Associated Baroreceptor Sensitivity in Response to Administration of NP

MAP fell immediately after the rapid infusion of bolus NP,

reaching the lowest point within 35 to 40 sec in all cats. This

initial fall of MAP was not affected by bilateral lesions of rFN.

Table 5 shows the maximal responses of MAP and HR to administration

of NP in Groups I-III. The maximal decrease in MAP was approximately

50 mmHg in all three groups, before or after lesions of rFN. The

rapid fall in MAP was accompanied by a reflex cardioacceleration of

approximately 20 beats/min at the lowest MAP level in all three

groups before lesions of FN. This increment in HR was reduced

significantly after bilateral rFNL (Group I). The change in HR per

unit change in MAP at the lowest MAP level was reduced by bilateral

rFNL from +0.41 ± 0.05 to +0.25 + 0.04 beats/min/mmHg (p < 0.05).

Figure 12 demonstrates the linear regression curves for change

in HR as a function of change in MAP during the fall in MAP induced

by infused NP in Groups I-III. In Group I, the original slope

68

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69

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71

GROUP I B i l a t e r a l rFNL

GROUP II Incomple te rFNL

GROUP III Sham L e c i o n t of FN

CO » .o

CO

I 10

» 01 c

N P - 1 y» ( - 3 0 2 1 1 3 2 ) * ( - 0 S 3 t 0 0 4 )

N P - 2 y« (-2 09 to 96).(-0.31 t o 03) «

I I I I

20-

10-

NP y«

- 4 0 - 3 0 - 2 0 - 1 0 I I I 1 I 1 1 I

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20-

10-

N P - 1

N P -y = (

- 4 0 I I 1 I

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Change in Mean Arterial Pressure (mmHg)

72

(NP-1, -0.53 ± 0.04) was decreased significantly after bilateral rFNL

(NP-2, 0.31 + 0.03, P < 0.01). The slopes were not affected by

incomplete or sham lesions of rFN in the other two groups.

Effects of rFN Lesions on Cardiovascular Responses During Recovery After NP-induced Hypotension

In all cats, recovery of MAP from NP-induced hypotension before

lesions of rFN could be separated into two phases (Figure 13): an

early, rapid phase and a late, slow phase. After bilateral rFNL, the

early, rapid phase in recovery was blunted, and complete recovery was

prolonged. Table 6 presents the time courses of MAP changes in

Groups I-III. As displayed in the table, the time course of MAP

recovery was prolonged by bilateral rFNL, but not affected by

incomplete rFNL or sham lesions of rFN.

In Group I, changes in MAP and HR were measured at 25, 50, and

100 sec after MAP reached the lowest level. As presented in Table 7,

at each measurement, the recovery in MAP was less after bilateral

rFNL. Before lesions of rFN, the cardioacceleration, initiated

during the fall in MAP, was maintained during much of the recovery

phase. After bilateral rFNL, this cardioacceleration during the

recovery phase was abolished and, at 50 and 100 sec, the HR was even

slower than the resting level. Femoral BF was measured in 6 of the

12 cats in Group I. Resting femoral BF was 10.5 ± 2.2 ml/min and was

not altered after bilateral rFNL (9.5+2.0 ml/min). The changes in

MAP, HR, and femoral R of these 6 cats measured at 25, 50, and 100

sec after lowest MAP are presented in Table 8. The effects of

74

100

X E E 3 50 -0. <

b'

Before rFNL After bilateral rFNL

T 4 6

Time From Nitroprusside (NP) Infusion (min)

75

z Ut u

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<

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MH

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m u 3 O

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cs I

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CN

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00

+ 1 CN

in

00

+

in

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+ 1 O 1-H CM

ON

I +1 +1 CJN

+ 1 in CN

CO

+ 1 CN CN

CM in

CN

+1 CN O

VO 1-H

+ 1 +1 O

o CM

ON

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CN

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OS

+1 CO

i n

+1 o CN

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CO I-H

+1 cys

r^

+ 1 f-H >d-

20*

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+

222

in CN

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o o

MH

o 4-)

in 3 o o d-d-v 3

•H CU

3 * -H

E PH O < 1-H

3 4-> -H CD J3 0) 4->

o > 1-H

& E O O O U r H

MH O

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T-\ P H

4-> S 3 ^ -cu >H

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CO CU 3

o • CO

4-> CO

CL O

V

CO * > *

CN

76

Table 7

Influence of Bilateral rFNL on MAP and HR Responses During Recovery After NP-induced Hypotension (n = 12)

Before rFNL After Bilateral rFNL

(NP-1) (NP-2)

Timet AMAP AHR AMAP AHR

0 sec

25 sec

50 sec

100 sec

-51 + 2

-29 + 2

-19 + 1

-13 + 2

+20 + 2

+11 + 2

+6 + 1

+3 + 1

-52 + 3

-37 + 3*

-29 + 2*

-22 + 3**

+12 + 2*

+2 + 3*

-6 + 1**

-7 + 1**

Values (mean + S.E.M.) are changes from resting values at different time periods after lowest MAP (0 sec). * p < 0.05, ** p < 0.01 between NP-1 and NP-2. t measured from lowest MAP level.

77

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78

bilateral rFNL on MAP and HR changes in the 6 animals were also the

same as in the whole group. NP reduced the femoral R (-1.5+0.9

units; unit = mmHg x min/ml) at the lowest MAP level before rFNL.

The femoral R was augmented greatly at 50 sec (+2.8+1.2 units) and

at 100 sec (+3.1 j: 1.4 units). Although bilateral rFNL did not alter

the resting femoral R (15.4 + 2.1 vs. 15.1 j 2.3 units), it did widen

the deficit in femoral R induced by NP infusion, and a relatively

weak vasoconstriction was not seen until 100 sec. As shown in Table

8, femoral vasoconstriction during recovery was impaired signifi

cantly after bilateral rFNL.

Effects of Captopril and Propranolol on Cardiovascular Responses to NP-induced Hypotension

Table 9 shows the effects of captopril on resting MAP and HR and

the cardiovascular responses to infused NP in sham-operated cats in

Groups VI. Captopril did not change the resting MAP and HR or reflex

cardioacceleration after infusion of NP. The time course of MAP

recovery from NP-induced hypotension was not affected by captopril

(Table 9). As shown in Table 10, treatment with PPN decreased the

resting HR significantly from 209 ± 12 to 164 +_ 6 beats/min (p <

0.01). The reflex cardioacceleration was almost abolished by PPN.

There was a tendency for the time course for MAP recovery to be

prolonged with PPN, but the differences were not significant.

79

Table 9

Influences of Captopril on Resting MAP and HR, Maximal Changes in MAP and HR, and Time Course of MAP Recovery After NP Administration

Captopril-

NP-1 NP-2

Resting MAP (mmHg)

Resting HR (beats/min)

Maximal AMAP (mmHg)

AHR (beats/min)

AHR /AMAP (beats/min/mmHg)

25% Recovery (sec)

50% Recovery (sec)

80% Recovery (sec)

130 + 8

197 ± 14

-50 ± 2

+16 + 2

+0.33 ± 0.05

24 -h 8

62 ± 12

143 + 21

120 + 9

194 -i 13

-50 + 2

+13 + 2

+0.27 + 0.04

23 + 6

57 + 12

152 + 22

Values are mean +_ S.E.M. +AHR measured at time of maximal AMAP. t administered between NP-1 and NP-2.

80

Table 10

Effects of Propranolol on Resting MAP and HR, Maximal Changes in MAP and HR, and Time Course of MAP Recovery After NP Administration

Propranolol!

NP-1 NP-2

Resting MAP (mmHg)

Resting HR (beats/min)

Maximal AMAP (mmHg)

AHR" (beats/min)

AHR"^/AMAP (beats/min/mmHg)

25% Recovery (sec)

50% Recovery (sec)

80% Recovery (sec)

157 + 5

209 + 12

-47 + 3

+18 + 4

+0.41 + 0.09

1 2 + 3

33 + 10

118 + 16

145 ± 1

164 + 6*

-44 + 2

+5 + 1

+0.31 i 0.03

1 5 + 2

48 + 11

150 + 23

Values are mean ^ S.E.M. " AHR measured at time of maximal AMAP. t administered between NP-1 and NP-2. * p < 0.05 between NP-1 and NP-2.

81

Effects of Bilateral rFNL on Baroreceptor Sensitivity During PE-induced Elevation in MAP

In Group VI, PE resulted in an immediate increase in MAP,

inducing a prominent reflex cardiodeceleration. The maximal

increment in MAP was +52 +_ 5 mmHg before and +43 +_ 5 mmHg (p < 0.05)

after bilateral rFNL. Because of this discrepancy, baroreflex

cardiodeceleration was examined at the same increment in MAP (30

mmHg) (Figure 14). Thus, the recorded decrease in HR per unit

increase in MAP was -0.65 ± 0.19 beats/min/mmHg before rFN lesions,

increasing significantly to -1.09 ± 0.29 beats/min/mmHg (p <0.05)

after bilateral rFNL.

-1.5-1

83

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Before After

Bilateral rFNL

CHAPTER IV

DISCUSSION

Part I. Stimulation of the rFN Inhibits Parasympathetic Activation Induced by Elevated MAP

The first part of the present study demonstrates that electrical

rFNS inhibited baroreflex cardiodeceleration induced by elevations in

MAP in the anesthetized, paralyzed, and artificially ventilated cat.

Pretreatment of the cat with PPN attenuated, but did not abolish the

fastigial pressor response or the fastigial suppression of the reflex

cardiode-celeration. The results indicate that rFNS can inhibit

parasympathetic activation induced by elevated MAP.

Participation of the Parasympathetic Nervous System in Fastigial Pressor Response

The fastigial pressor response differs from that evoked by

stimulating the brainstem, the latter having usually an associated

decrease in HR (Miura and Reis, 1969a; Miura et al., 1986). Thus,

elevating the arterial blood pressure by stimulating the brainstem

elicits a reflex deceleration of HR, as is observed usually when

arterial blood pressure is elevated by other means such as

administration of PE or aortic occlusion (Abboud and Thames, 1983),

This suggests that pressor centers in the brainstem do not mediate

84

85

direct reciprocal suppression of parasympathetic output. There are

two possible explanations for the unique association of increased HR

with elevated MAP during rFN stimulation. First, the prevailing

excitation of the sympathetic nervous system overwhelms the

cardiovagal reflex. Second, there is a direct inhibitory effect on

the parasympathetic nervous system, in addition to sympatho

excitation, during rFN stimulation. Early studies by Achari and

Downman (1970) and Doba and Reis (1972b) attributed this fastigial

acceleration of HR to a pure excitation of the sympathetic nervous

system, because they found that the fastigial HR increase was blocked

by PPN. The possibility of a parasympathetic contribution was either

rejected (Achari and Downman, 1970) or not mentioned (Doba and Reis,

1972b). Although they have suggested that sympathetic activation and

withdrawal of vagal cardiac inhibition contribute dually to the

fastigial cardioacceleration, Lisander and Martner (1971) did not

show a direct suppression of vagal effect by fastigial stimulation.

All three groups failed to present statistical analysis of their data

to support their statements.

In the present study, results are expressed quantitatively to

show that rFN stimulation can suppress parasympathetic activation

during elevation of MAP. Propranolol is a nonspecific S-adrenergic

blocking agent (Jose, 1966; Lucchesi et al., 1966). Administration

of PPN in cats blocks the cardiac ^-adrenergic receptors, resulting

in a significant reduction in resting HR in the cat. The decrease in

MAP could be slight because of a compensatory augmentation of

peripheral vascular resistance (Nies et al., 1973). Although the

86

dose-related increases in MAP and HR evoked by rFN stimulation were

not altered by PPN, the actual increases in both parameters were

reduced. The reduction in HR response could be explained easily by

the blockade of the fastigial sympathetic excitation with PPN. The

reduction in MAP may result from a combination of lessened HR and

contractility responses and an already elevated resting vascular tone

after PPN. The failure of P-adrenergic blockade to abolish

acceleration of HR indicated a direct inhibition of the parasympa

thetic activity. The resting HR is under the dual control of both

the sympathetic and parasympathetic innervations (Abboud and Thames,

1983); after administration of atropine, the resting HR increased

15-20 beats/min in the present study. This is in agreement with the

report of Lisander and Martner (1971) that atropine (0.5 mg/kg)

increased resting HR up to 50 beats/min in cats anesthetized with

chloralose. Thus, the acceleration in HR during elevated MAP after

PPN resulted from a suppression of reflex vagal inhibition of HR.

Inhibition of rFNS on Reflex Cardiodeceleration

The baroreflex cardiodeceleration induced by elevated MAP after

PE was not affected by PPN, suggesting that this reflex is mediated

primarily through the parasympathetic nervous system in the

anesthetized cat. This is supported by the fact that the reflex was

almost abolished by pretreatment with atropine alone. This PE-

induced reflex cardiodeceleration was suppressed by concurrent rFN

stimulation both before and after administration of PPN. This

87

fastigial suppressive effect observed before ^-adrenergic blockade

was consistent with previous observations in that rFN stimulation

inhibited baroreflexes (Achari and Downman, 1970; Lisander and

Martner, 1971; Miura and Reis, 1971). The present study is the

first, however, to analyze the data quantitatively . It is clearly

presented here that the suppression can be accomplished with a very

low stimulus intensity (25 wA, 0.1 msec, 50 Hz) and amplified with

increases in stimulus intensity. After blocking the cardiac

-adrenergic receptors with PPN, this fastigial suppressive effect

was almost entirely preserved. This result suggests strongly that

rFN stimulation can suppress reflex cardiodeceleration through

inhibition of the parasympathetic activation induced by elevated MAP.

As in the period before infusion of PPN, fastigial suppression of

parasympathetic activation was effective at a very low intensity and

was amplified with increases in stimulus intensity.

The concept that rFN stimulation can inhibit parasympathetic

activation in addition to exciting the sympathetic nervous system has

never been demonstrated with strong experimental data. In a largely

neglected short report, Hockman et al. (1970) showed in a figure that

fastigial stimulation could abolish reflex cardiodeceleration induced

by aortic clamping in cats with the spinal cord transected at C^.

The stimulus intensity they used was high (500 yA); thus, it could

not be excluded that the effect might have resulted from current

spreading to other areas such as the brainstem. Because spinal

transection eradicated not only B- but also a-adrenergic output to

the heart and peripheral vasculature, the arterial blood pressure had

88

to be kept stable by infusing dextran. In the present study, only

the 6-adrenergic receptors were blocked, and the blood volume was

undisturbed so that pure interaction between fastigial stimulation

and parasympathetic activation could be tested. In another

overlooked report, Achari et al. (1973) showed in an experiment

performed in 3 conscious cats that the fastigial suppression of

reflex cardiodeceleration persisted after administration of PPN. The

size of the experimental group was inadequate, however, for data

analysis and that rFN stimulation can inhibit parasympathetic

activation was not emphasized by the authors.

The Autonomic Mediation of Reflex Cardiodeceleration in the Cat

Administration of atropine abolished both fastigial cardio

acceleratory and PE-induced reflex cardiodeceleratory responses in

cats pretreated with PPN. This result verified the adequacy of

3-adrenergic blockade by PPN and indicated that both responses under

this circumstance resulted from inhibition of the parasymapthetic

activation. Thus, although the present study did not disprove the

contribution of sympathetic excitation to the fastigial suppression

of reflex cardiodeceleration, it proved that this suppression could

be accomplished by inhibiting parasympathetic activation when rFN was

stimulated.

The suppressed reflex cardiodeceleration was unmasked with the

termination of rFN stimulation, whether alone or concomitant with

infusion of PE, indicating a short duration of this inhibitory

89

effect. It might suggest also the absence of the fastigial

interference of the cardiodeceleratory reflex that occurs physiolo

gically during abnormal elevation of blood pressure. The tonic

influence of the rFN region on parasympathetic activity was not

tested in this study; however, some suggestive results were obtained

in the second part as discussed.

Summary

The fastigial inhibitory effect on baroreflex cardiodeceleration

parallels that on the vagal-mediated defecation and micturition

reflexes (Martner, 1975b). In these situations, the effects of

stimulation of rFN are not at all dependent in the integrity of

sympathetic pathways. It can be concluded thus that this particular

cerebellar area is involved in both sympathetic and parasympathetic

autonomic mechanisms, and affects multiple organ systems.

Part II. Bilateral rFNL Impair Cardiovascular Responses to Transient Hypotension and

Alter Baroreceptor Sensitivity

The second part of the present study demonstrates that bilateral

lesions of the rostromedial FN (rFNL) in anesthetized, paralyzed, and

artificially ventilated cats can impair sympathetic reflex cardio

acceleratory and vasoconstrictor responses to a transient hypotension

activating primarily arterial baroreceptors. The altered cardio

vascular responses seen with bilateral rFNL were not found in animals

with incomplete rFNL or sham lesions of the rFN.

90

Involvement of the rFN Area in Blood Pressure Recovery from Different Types of HypotensioiT"

Previous studies have demonstrated that bilateral rFNL alter

cardiovascular responses to orthostatic tilt in the cat and the

monkey (Doba and Reis, 1974; Huang et al, 1977; Koyama et al., 1981)

and to hemorrhagic or endotoxic shock in the dog (Lutherer et al.,

1983a). As noted by Doba and Reis (1974), the tilt-induced

orthostatic response involves both the baroreceptor and vestibular

inputs, and bilateral section of the vestibular nerves impairs the

tilt response to the same extent as bilateral rFNL. During the

relatively long-term episodes of hypotension induced by hemorrhage or

endotoxin, because of the decrease in actual or effective blood

volume, both baroreceptors and volume receptors are activated, and

secretion of vasomotor hormones is triggered. Stimulation of FN has

been shown to elevate plasma levels of renin (Koyama et al., 1980)

and AVP (Del Bo, et al., 1983b). The studies by Lutherer et al.

(1983b) suggested that cerebellectomy impairs recovery from these

types of hypotension, in part, by limiting the humoral response.

Therefore, in the tilt or shock models, the influence of the rFN area

on the autonomic responses to hypotensive challenges induced by

baroreceptor unloading alone could not be assessed separately.

Factors Involved in Cardiovascular Responses to Transient Hypotension Induced by NP

Plasma levels of both renin and AVP have been shown to increase

after a 30 to 60-min infusion of a high dose (80-160 yg/kg/min) of NP

91

in different species (Francis et al., 1983; Zubrow et al., 1983).

Long-term, high dose NP perfusion leads to pooling of blood and a

resultant hypovolemia, which triggers secretion of renin and AVP.

Captopril failed to affect the recovery of MAP in our cats,

indicating that the renin-angiotensin system did not play a major

role in mediating MAP recovery. Thus, the vasoconstriction results

primarily from an enhanced a-adrenergic, sympathetic output.

Although plasma levels of AVP were not measured in the present study,

it has been shown by others that rapid unloading of the baroreceptors

in animals with intact vagi, a model similar to ours, failed to

increase release of AVP (Thames and Schmid, 1979).

NP is a rapid-onset, short-duration, vasodilatory agent

(Blashchke et al., 1980). Rapid intravenous infusion of bolus NP in

the cat induced an immediate decrease followed by a rapid recovery in

MAP. Because of the nature of this type of hypotension, the afferent

information should originate primarily from the high-pressure,

arterial baroreceptors. The vestibular pathways were not involved,

because the cat was paralyzed and placed in a stereotaxic frame and

paralyzed. Thus, the reflex cardioacceleration and vasoconstriction

in the cat are autonomic responses to baroreceptor unloading. The

reflex cardioacceleration results primarily from the 3-adrenergic,

sympathetic output, which is substantiated by the abolishing effect t

of PPN on this reflex.

92

Effects of Bilateral rFNL on Cardiovascular Responses to NP-induced Hypotension

The initial decrease in MAP in response to NP was not affected

by bilateral rFNL. This parallels findings in the shock studies, in

which neither the loss of blood necessary to reduce MAP to 50 mmHg

(Lutherer et al., 1983a; 1983b) nor the initial decrease induced by

endotoxin (Janssen et al., 1981) was affected by cerebellectomy or

rFNL. In tilt studies (Doba and Reis, 1974; Huang et al., 1977),

bilateral rFNL resulted in a greater initial decrease in blood

pressure during tilt. This discrepancy might result also from the

vestibular involvement during orthostatic tilt (Doba and Reis, 1974).

Bilateral rFNL abolished the cardioacceleration and impaired the

vasoconstriction during the recovery. These are in agreement with

the results in tilt studies in which bilateral rFNL impaired reflex

cardioacceleration (Huang et al., 1977) and vasoconstriction (Doba

and Reis, 1974). Thus, regardless of the different inputs between

tilt- and NP-induced hypotensions, the integrity of the rFN is

required for adequate chronotropic and vasoconstrictor responses

during the recovery. Pretreatment with PPN impaired the recovery of

MAP only partially, suggesting that both Or- and S-adrenergic

components of the sympathetic outputs are essential to the recovery.

Tonic Influences of the rFN Area on Resting HR and Baroreceptor Sensitivity

Alteration of resting MAP or HR with bilateral rFNL in cats has

not been reported by other investigators. The failure to see a

93

significant decrease in blood pressure after bilateral lesions of rFN

or cerebellectomy suggests that there is compensation by other

systems or that the rFN lacks tonic influence on the cardiovascular

system. In the present study, although resting MAP was not altered

by bilateral rFNL, the resting HR was decreased. The decrease in

resting HR after bilateral rFNL was observed recently in a study of

spontaneously breathing cats (Williams et al., 1986). These results

suggest that the rFN does exert a tonic influence on the

cardiovascular system. The fact that rFNL attenuates reflex

cardioacceleration during the decrease in MAP indicates further that

the rFN region has an early influence on the cardiac chronotropic

response to hypotension.

As presented in the first part, electrical stimulation of the

rFN exerts an inhibitory effect on parasympathetic activation induced

by sudden elevation of blood pressure. In this part of the present

study, baroreflex cardiodeceleration in response to elevations in MAP

was augmented after bilateral FNL. This result suggests that lesions

of the rFN may remove the possible tonic inhibitory effect of this

nucleus on parasympathetic activity. Since NP-induced hypotension is

associated with a withdrawal of parasympathetic inhibition and an

enhancement of sympathetic activity (Chen et al., 1982), a decreased

inhibition of parasympathetic activity after FNL may contribute also

to the impairment of MAP recovery.

Electrical stimulation of rFN inhibits reflex cardiodeceleration

in response to baroreceptor loading as shown in the first part of

this study as well as by Achari and Downman (1970), Hockman et al.

94

(1970), Lisander and Martner (1971) and Miura and Reis (1971). The

effects of lesions of rFN on pure baroreceptor responses has not been

explored except for an unsupported statement by Lisander and Martner

(1971) that bilateral lesions of FN failed to affect cardiovascular

responses to carotid baroreceptor unloading. In contrast, the

present study showed that bilateral rFNL impaired reflex

cardioacceleration in response to rapid baroreceptor unloading and

augmented cardiodeceleration to baroreceptor loading. This is

consistent with the finding of Huang et al. (1977) that the

cardioacceleration during recovery from tilt was impaired in cats

with acute bilateral rFNL, even although one cannot exclude the role

of vestibular afferents in that model. That both the ascending and

descending limbs were altered by rFNL may suggest that the cerebellum

exerts a tonic influence on baroreceptor sensitivity.

Summary

Thus, although the nature of the influence of the rFN area

remains to be elucidated, the second part of this study has

demonstrated three major findings regarding the influences of this

cerebellar area on the cardiovascular system. First, it influences

tonically the control of resting HR. Second, it is important in

mediating sympathetic reflex cardio-acceleratory and vasoconstrictor

responses to a transient, isovolemic hypotension mediated primarily

by the arterial baroreceptors. Third, it influences both the

ascending and descending limbs of the baroreceptor sensitivity curve

95

General Discussion

It can be concluded from the present study that stimulation of

rFN inhibits parasympathetic activity and excites the sympathetic

nervous system. Furthermore, bilateral rFNL impaired sympathetic and

augmented parasympathetic activities during MAP changes; and the

integrity of the rFN region was important for the maintenance of

normal baroreceptor sensitivity. The neural pathways by which these

interactions at the level of FN can alter autonomic output remain to

be delineated. As described hereafter, anatomical studies suggest

pathways that could be involved, but their physiological function has

not been well studied. Moreover, it is yet to be determined whether

the neurons in or fibers passing through the rFN region, or both, are

involved in these interactions.

Recent preliminary reports from Reis's laboratory (Chida et al.,

1985; Chida et al., 1986) suggested that the pressor response

elicited with electrical stimulation of the rFN involved fibers of

passage through this region rather than cells within it. These

studies employed microinjection into the rFN of low doses (up to 100

nmole in 100 nl) of the excitatory amino acids 1-glutamate (1-glu),

1-aspartate (1-asp), kainic acid (KA), dl-homocysteate (dl-hom), and

N-methyl-dl-aspartate (NMDA) in the rat (Chida et al., 1985).

Although 1-glu or 1-asp had no effect, KA, dl-hom, and NMDA all

elicited an unexpected reduction in both MAP and HR. The authors

termed these cardiovascular changes the fastigial depressor response

as opposed to the fastigial pressor response elicited by electrical

stimulation of rFN. When the rFN neurons had been lesioned by

96

ibotenic acid, the pressor response to electrical stimulation was not

altered, but the KA-induced depressor response was abolished. The

depressor response was not blocked by atropine, but was abolished by

spinal cord transection at C, or by local injection of a NMDA

antagonist. The authors concluded that a) the pressor response to

electrical stimulation of rFN was caused by fibers projecting into or

through rFN (origin not identified), and b) the fastigial depressor

response to some excitatory amino acids was caused by sympatho-

inhibition and depended in part on the NMDA receptors. These

findings are in contrast to an earlier observation made by Dormer and

Stone (1977). Microinjection into rFN of 1-glu (50-100 yl) in the

dog resulted in an elevation with a vagally mediated cardio

deceleration, suggesting that the pressor response involved cells of

origin in the FN. One might argue that the volume for microinjection

used in the latter study was too large and that the local tissue

might be damaged by this large volume of fluid. There are three

valid points against this argument. First, control injection with

manitol at the same volume did not elicit any change in MAP or HR.

Second, the size of the dog's brain and hence the rFN area are much

larger than their counterparts in the rat. Third, it is unlikely

that damaging the rFN and surrounding area could evoke a pressor

response. Because of the discrepancy between these reports and the

lack of similar experiments in the cat, it cannot be ascertained what

neuron groups are involved in the responses observed in the present

study. Electrophysiologically, Ghelarducci (1973) showed changes in

firing rate of the rFN neurons in decerebrate cats in response to

97

tilt, a positional alteration known to induce cardiovascular

responses (Doba and Reis, 1974). More recently, Lutherer et al.

(1986) have documented changes in the firing rate of cells within the

rFN during cardiovascular challenges, but the efferent modality of

the cells examined is unknown.

Separate anatomical studies have depicted the afferent inputs to

and efferent projections from the FN. Although the physiological

significance of most of these pathways has yet to be determined,

possible roles of some of these pathways in conveying the fastigial

effects in the present study cannot be excluded. Because the FN is

involved in multiple somatic and autonomic functions, the pathways

mentioned below may serve to mediate the fastigial responses observed

in this study or other fastigial effects.

Afferently, the fastigial nucleus receives inputs from the

cerebellar cortex, spinal, and various other nuclei in the brainstem

(Ito, 1984). Three types of afferent fibers to the FN were shown in

the cat using the Golgi and Golgi-Kopsch methods (Matsushita and

Iwahori, 1971). Type A have the largest diameter and are the

Purkinje axons. Type B (medium-sized) and type C (very fine) are

fibers of passage that give off collaterals to FN. Studies using

retrograde transport of horseradish peroxidase (HRP) from localized

injection into the FN in the cat demonstrated that the FN receives

projections from the Purkinje cells in the ipsilateral vermis

(Courville and Diakiw, 1976; Ruggiero et al., 1977; Carpenter and

Batton, 1982). The fibers originate from lobules I through X

(Ruggiero et al., 1977) and are distributed topographically to the

98

nearest region of the FN (Courville and Diakiw, 1976). Thus, the

fibers arising from the anterior vermis project to the rostral FN and

those from the posterior FN project to the caudal FN (Courville and

Diakiw, 1976).

The spinal inputs to FN were revealed by degeneration studies

(Matsushita and Ikeda, 1970; Matsushita and Ueyama, 1973), in which

hemisection of the cervical cord in the cat, rabbit, and rat showed

that spinocerebellar mossy fibers give off collaterals to the FN.

From the brainstem, fibers arising bilaterally from the caudal part

of the medial vestibular nucleus (MVN) form the largest number of

inputs to FN (Carpenter and Batton, 1982). Carleton and Carpenter

3 (1983) by injecting HRP and [ H]leucine into the vestibular complex

in the cat found no projection fibers arising from the inferior (IVN)

and lateral (LVN) vestibular nuclei. Olivary inputs to the FN

through the climbing fibers arise contralaterally from the medial

accessory olivary nucleus (nucleus 3 and the dorsomedial cell column)

(Ruggiero et al., 1977). The FN receives clearcut inputs also from

the entire lateral reticular nucleus (LRN) as depicted by the HRP

method in the cat (Dietrichs and Walberg, 1979). Small numbers of

inputs arise bilaterally from the paramedian reticular nucleus (PRN),

nucleus prepositus, and nucleus of Roller (Carpenter and Batton,

1982). Direct inputs from the NTS to the FN have not been reported;

however, retrograde labeling in the cerebellar vermis of HRP injected

in the NTS has been reported (Somana and Walberg, 1979). Scanty

bilateral afferent projections to FN from the dorsal motor nucleus

have been shown in the cat with HRP method (Zheng et al., 1982).

99

Efferently, the rFN projects to other parts of the central

nervous system through two major routes: the contralateral uncinate

fasciculus and the ipsilateral restiform body (Batton et al., 1977).

Autoradiography (Andrezik et al., 1984; Carpenter and Batton, 1982)

and retrograde transport of HRP (Ross et al., 1981) revealed that the

efferent fastigial pathways include fibers to the nucleus of the

tractus solitarius (NTS), fastigiovestibular fibers, fastigio

reticular fibers, fibers to perihypoglossal nuclei, fastigiopontine

fibers, fastigiospinal projections, and ascending fastigial efferent

projections.

When HRP was injected unilaterally into the intermediate NTS

(Ross et al., 1981), there was extensive retrograde labeling

contralaterally in the rostral portion of FN. This is in accordance

with the finding from an earlier autoradiographic study (Moolenaar

and Rucker, 1976) in which the NTS was found to receive projections

from the rostral portion of FN. Recently, Andrezik et al. (1984)

showed in a autoradiographic study that FN efferent fibers project

also to the dorsolateral parts of the NTS (parasolitary area) in the

dog.

Findings based upon retrograde transport of HRP in the cat

(Carleton and Carpenter, 1983), and consistent with autoradiograghic

observations (Batton et al., 1977; Carpenter and Batton, 1982)

indicated that the LVN and IVN receive inputs from all parts of the

cerebellar vermis through the FN. Projections to the LVN arise

preferentially from the rostral part of the ipsilateral FN, whereas

fibers projecting to IVN arise largely from central regions of the

100

contralateral nucleus. The MVN receives few afferents from the FN.

The fastigiovestibular pathway has been confirmed electrophysi

ologically (Akaike, 1983) with extracellular and intracellular

recordings of LVN neuronal activity when the FN was stimulated.

Electrical stimulation of the ipsi- and contralateral FN evoked

monosynaptic excitation of neurons in the ventral LVN.

Fastigioreticular fibers arise predominantly from the rostral

parts of the FN, are primarily crossed, and project to: a) medial

regions of nucleus reticularis gigantocellularis, b) parts of the

caudal pontine reticular formation, c) the dorsal PRN, and

d) portions of the magnocellular part of the LRN in the cat (Batton

et al., 1977; Elisevich et al., 1985) and also the dog (Andrezik et

al., 1984). Fastigiopontine fibers are crossed but separated from

the uncinate fasciculus. They pass through the middle cerebellar

peduncle and terminate in the dorsal pontine nuclei (Batton et al.,

1977), which in turn feed back to the cerebellar cortex (Brodal and

Jansen, 1946).

Fastigiospinal fibers cross contralaterally and descend

ventrally to the lateral funiculus of the spinal cord (Batton et al.,

1977). Local injections of HRP into the spinal gray of the cat

(Fukushima et al., 1977; Matsushita and Hosoya, 1978) disclosed that

contralateral FN neurons were associated primarily with the 02-0^

segments. Physiologically, antidromic stimulation of the cervical

spinal cord and direct stimulation of the FN present evidence that

axons of the fastigiospinal neurons contact mono-synaptically with

motoneurons at the 02-0^ level (Wilson et al., 1978).

101

Ascending fastigial projections to various parts of the

forebrain have been suggested in an early degeneration study in the

cat (Harper and Heath, 1973); the areas with possible fastigial

inputs included the hypothalamus, central thalamic nuclei, septal

region, and orbital gyri. Evidence obtained by autoradiographic

methods (Batton et al., 1977) revealed crossed ascending fastigial

projections from the caudal FN to ventral posterolateral and ventral

lateral thalamic nuclei, suggesting that the ascending fastigial

impulses are relayed probably to both the primary somesthetic and

motor cortex.

Although anatomical studies have demonstrated multiple fastigial

projections to various nuclei in the brainstem, Miura and Reis

(1969a; 1970) showed that among the sites lesioned, only bilateral

destruction of the rostral paramedian reticular nuclei (PRN) and

restiform bodies (route of fastigial efferent pathways) abolished the

fastigial pressor response. Lesions of the intermediate NTS, caudal

PRN, LRN, inferior olivary nuclei, and nucleus reticularis giganto

cellularis did not abolish the pressor response. Bilateral lesions

of the PRN also abolished the depressor response induced by

stimulation of the carotid sinus nerve (Miura and Reis, 1971).

In previous electrophysiological studies, Miura and Reis (1968;

1969b) had found that both the PRN and the intermediate NTS showed

monosynaptic responses triggered by stimulation of the carotid sinus

nerve fibers. On the basis of the electrical and anatomical

relationships between the carotid sinus and the PRN and between the

PRN and FN, it seemed reasonable that bilateral destruction of PRN

102

would abolish responses evoked by stimulation of the FN or carotid

sinus nerve. Nevertheless, a recent study by Dormer et al. (1986)

showed in the dog that bilateral thermal lesions of the PRN as well

as the intermediate NTS, LRN, nucleus reticularis gigantocellularis,

and other areas in the medulla did not alter the fastigial pressor

response. Nevertheless, the negative findings could not exclude the

involvement of these areas in mediating tonic vasomotor control and

baroreflexes. Lesions of the A5 area and restiform bodies abolished

the increases in MAP, HR, maximal left-ventricular pressure and

ventricular contractility elicited by rFN stimulation. The

discrepancy in the effect of lesioning the PRN between the two

studies in different species can not be explained at the present.

The A5 area is at the pontomedullary junction between the Vllth

cranial nerve and the superior olive (Dahlstrom and Fuxe, 1964). It

is one of the norepinephrine-containing cell groups (together with

Al, A2, A6, and A7 areas) projecting to the intermediolateral (IML)

cell column of the spinal cord (Lowey et al., 1979b). Electrical

stimulation of the A5 area with 5 PA resulted in immediate increases

in arterial blood pressure (Lowey et al., 1979a). Thus, it is

possible that one of the relay areas of the canine fastigial pressor

response is the A5 cell group, which projects to and activates the

preganglionic sympathetic vasomotor neurons of the spinal cord. In

animals with intact vagi, termination of A5 stimulation resulted in

decreases in blood pressure and HR (Lowey et al., 1979a). It is

possible that the A5 area can suppress the vagal inhibitory effect on

the heart during stimulation.

103

McAllen (1985b) was able to abolish or severely impair the

fastigial pressor response by thermal lesions of or application of

glycine to the glycine-sensitive area of the ventrolateral medulla in

the cat. The glycine-sensitive area has been shown by the HRP method

(Amendt et al., 1979) to project to the IML of the spinal cord.

There was ample direct projection from the FN to the PRN and a more

modest projection to the ventrolateral medulla (Moolenaar an Rucker,

1976). Although the effect of PRN lesions on the fastigial pressor

response is still controversial (Miura and Reis, 1970; Dormer et al.,

1986), a possible role of the PRN as a conduit for the fastigial

impulse to the ventrolateral medullary area cannot be excluded

(McAllen, 1985b). The glycine-sensitive area has been found also to

be involved in the baroreceptor reflexes. The firing activity of the

local neurons in the glycine-sensitive area could be inhibited by

baroreceptor stimulation (McAllen, 1985a); on the other hand, local

injection of the neuronal inhibitory agent bicuculline blocked the

baroreflexes induced by stimulation of the carotid sinus nerve

(Yamada et al., 1984). Because chemical application of glycine

depressed the neurons but not the axons, it can be concluded that the

glycine sensitive area serves also as a relay station of the

excitatory effect for the sympathetic nervous system evoked by rFN

stimulation. The widespread fastigial sympathoexcitation can be

mediated through this final (but not necessarily only) common

pathway.

The NTS has been known to be a major central integrative site

for cardiovascular reflexes (Abboud and Thames, 1983). This nucleus

104

receives projections from the carotid sinus nerve (Miura et al.,

1986), aortic depressor nerve (Ciriello et al., 1981), IML of the

spinal cord (Amendt et al., 1979), and FN (Andrezik et al., 1984;

Ross et al., 1981). Although lesions of the NTS did not block the

fastigial pressor response (Dormer et al., 1986; Miura and Reis,

1970), the involvement of the NTS, especially the intermediate zone,

in the mutual inhibitory interaction between the FN and the

baroreceptors cannot be excluded. Rather, it only indicated that the

fastigial pressor response does not depend on the integrity of this

baroreflex integration area. Electrical stimulation of the NTS can

elicit decreases in blood pressure and HR, and destruction of NTS can

increase blood pressure and abolish baroreflexes (Carey et al., 1979;

De Jong et al., 1979; Doba and Reis, 1973). Baroreceptor afferent

fibers converge on the NTS neurons, which then excite cardiac vagal

motoneurons and inhibit the sympathoexcitatory neurons (Howe, 1985).

The cardiac vagal motoneurons are located in the nucleus ambiguus and

the dorsal motor nucleus (Calaresu and Pearce, 1965; Struyker-Boudier

et al., 1982). Inhibitory impulses from the NTS neurons may suppress

the IML of the spinal cord directly or through the hypothetical

vasomotor center (Coote et al., 1975). A likely site for the

vasomotor center is the ventrolateral reticular formation of the

rostral medulla (McAllen et al., 1982), which is the glycine-

sensitive area mentioned above (McAllen, 1985b).

In conclusion, this dissertation study has demonstrated that

1) electrical stimulation of the ventromedial portion of the rostral

fastigial nucleus (rFN) inhibited parasympathetic activation induced

105

by elevated MAP; 2) electrical lesions of rFN on both sides

(bilateral rFNL) impaired sympathetic cardiovascular responses to

transient hypotension; 3) bilateral rFNL impaired reflex cardio

acceleration and augmented reflex cardiodeceleration during MAP

changes, thus altering baroreceptor sensitivity on both ascending and

descending limbs of the sensitivity curve; and 4) bilateral rFNL

reduced resting HR. These results indicate that the rFN region in

the cerebellum is important for central integration of activity of

the autonomic nervous system, involving both the sympathetic and the

parasympathetic components. Whether the local neurons or fibers of

passage through the rFN region, or both, are involved in these

fastigial effects cannot be determined at present. The output

modality for these fastigial effects is also uncertain; however, the

A5 cell area at the pontomedullary junction and glycine sensitive

area in the ventrolateral medulla seem to be strong candidates for

relay stations for the sympathoexcitatory component of the fastigial

effects. The route for the fastigial inhibition of the parasym

pathetic component is unknown. The A5 area is a possible relay site

because stimulation here inhibits vagally mediated cardio

deceleration. The NTS, especially the intermediate zone, can be

activated by input from the fastigial area and, in turn, suppress the

cardiac vagal areas in the nucleus ambiguus and/or the dorsal motor

nucleus. The PRN also cannot be discounted as a conducting region

for these responses.

Findings of the present and previous studies suggest that

neurons in or passing through the rostral pole of FN influence the

106

general autonomic activity. The integrity of this particular

cerebellar region has been shown to be essential to the maintenance

of normal sympathetic and parasympathetic responses to cardiovascular

challenges. This indicates both tonic and phasic influences of the

rFN region on the control of HR, blood pressure, and baroreceptor

sensitivity. The blood pressure changes induced in this study were

transient and isovolemic. In similar clinical situations, fastigial

suppression of parasympathetic activation may function with other

involved systems to reduce the severity and frequency of syncope

episodes induced by coughing or micturition reflexes or by Valsava's

maneuver in some patients. The fastigial sympathoexcitatory effect

may function to prevent severe hypotension in patients receiving

antihypertensive treatments. In shock, with or without blood loss,

the multiple fastigial autonomic effects would benefit the recovery.

With the dual influence on the autonomic nervous and vestibular

systems, the rFN region may be regarded as one of essential neural

areas for maintaining hemodynamic homeostasis. Patients undergoing

orthostatic hypotension episodes might have deficits in transmission

of impulses in the baroreceptor-brainstem-rFN circuit or in the rFN-

forebrain pathways. Because the FN is phylogenetically the oldest of

the four deep cerebellar nuclei (Beitz, 1982), further studies should

focus on disclosing the anatomical background for the physiological

effects of rFN. Proposals for future studies include recording the

firing rate of A2 cells in the intermediate NTS and the vagus nerve

during elevated MAP in intact cats, with or without concomitant rFNS,

and in cats with bilateral rFNL.

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