ROLE OF THE CAROTID BODY _

CHEMORECEPTORS IN THE REFLEX

REGULATION-0F THE ‘
CARDIOVASCULAR SYSTEM

Thesis for the Degree of Ph. D.
MICHIGAN STATE UNIVERSITY
PAUL EDWIN PARKER
1972

LIBRARY

Michigan Stan
University

 

This is to certify that the

thesis entitled

ROLE OF THE CAROTID BODY CHEMORECEPTORS IN THE
REFLEX REGULATION OF THE CARDIOVASCULAR SYSTEM

presented by

Paul Edwin Parker

has been accepted towards fulfillment
of the requirements for

Ph.D. degree in Physiology

 
    

Majo professor

Date November 15. 197L

0-169

     
     
   

  

y am‘ome av 1‘
HMS & SUNS'
500K BINDERY INC.

umm ORDERS
32mm”. gleam

IIL: 4-54- ,... 2, II

ABSTRACT
ROLE OF THE CAROTID BODY CHEMORECEPTORS

IN THE REFLEX REGULATION OF THE
CARDIOVASCULAR SYSTEM

BY

Paul Edwin Parker

While the reSpiratory responses to carotid body chemo-
receptor stimulation have been well defined, the cardiovascular
responses have not been thoroughly investigated. The aim of
this study was to determine the effects on canine forelimb,
intestine, kidney and coronary vascular resistance of perfus-
ing the isolated carotid bodies with hypoxic and/or hypercapnic
blood.

Perfusion of the carotid bodies and sinuses was provided
by a circuit containing an extracorporeal lung taken from
another dog. To change the O2 and CO2 content of the blood

perfusing the carotid bodies, the isolated lung was ventilated

with various 0 and CO gas mixtures in N Hypoxic-hyper-

2 2 2'
capnia was produced by ventilation with a gas mixture contain—

ing 0% 02 - 20% C02. Hypoxia alone was studied with 0% O2 -
5% C02. Hypercapnia alone was achieved with a mixture con—
taining 20% 02 - 20% C02. The use of the carotid sinus

perfusion circuit containing the isolated lung permitted

 

 

V 1
9-." AF‘HHO

-.
g ‘

novel Vtoi‘nlv‘v"
. v

-‘O-Q.:.H

::.C.-au-e Coho-ti

"23 “'61":
”(I .v. -t '

vi“.

i=.:e s~~~’< j b:
5

"=::--- '

:Ibuu‘he lncre I,
u

:“9..‘ .
"rm-5L1 n be :
En

re~ .
.aroud b0“
' Intestine

 

”5 ‘ran‘ I
'.‘ V 1 .
bills m“
H.
“3:: .
t‘ ' I
tin resic
51¢.

Paul Edwin Parker

rapid changes in carotid sinus blood gas content without
detectable changes in systemic blood gas concentrations.
The forelimb, intestine, kidney and coronary vascular beds
were perfused at constant blood flow to determine active
changes in vessel caliber.

The reflex responses to carotid chemoreceptor stimulation
were studied before and following vegotomy. Systemic arterial
pressure increased during hypoxic-hypercapnic chemoreceptor
stimulation before vagotomy and increased after vagotomy
during stimulation with hypoxia, hypoxic-hypercapnia and hyper-
capnia. Carotid chemoreceptor stimulation with hypoxic-
hypercapnic blood before vagotomy increased vascular resistance
in the kidney but caused no change in resistance in the fore-
limb, intestine or coronary vasculature. After vagotomy,
hypoxic, hypoxic-hypercapnic and hypercapnic stimulation of
the carotid bodies increased vascular resistance in the fore-
limb, intestine and kidney but not in the heart. The skin
and muscle vascular beds of the forelimb appeared to contri-
bute about equally to the increase in forelimb resistance.
Preliminary studies of the changes in vascular resistance in
the gracilis muscle and hindpaw (skin) vasculature indicated
a rise in resistance during hypoxic-hypercapnic chemoreceptor
stimulation following vagotomy.

Left ventricular contractile force decreased during

chemoreceptor stimulation before and after vagotomy but a

 

a In

.
,.
..'..' VCR-'R*;:h
m r. .uudvE

—-.a.—-uu o
a

l'vvflw' 0 v
' C

'1
,

D
D

‘ I
lfivl‘iq “hp—llflvo
.L.--‘ vet's-‘5- _._

H~A.--._
.

--~-....- .

nu ,
' ‘ “Yp;_
"" “'\-- -u.
- ‘
Il.:v- ”Sc/fivg "
-¢-..,. ~‘GQbu \ ..
' .
"*IA'

3““ d" :...e' 'V:
u». u.. ‘ ' u
.; 3‘34 r :“"v-
T“‘--~‘ E -..,.‘ .

A '5‘.
..

"'51:“ to the i

e~.,_'
.‘.l'- ‘ I-

.....g the pr‘

 

Paul Edwin Parker

larger reduction in contractile force was observed following
vagotomy. Heart rate was not consistently affected by
carotid chemoreceptor stimulation either before or after
vagotomy.

The increase in vascular resistance observed in the
kidney before vagotomy and in the forelimb, intestine and
kidney after vagotomy appeared to be a sympathoadrenal
mediated response to carotid body chemoreceptor stimulation.
These studies indicate that hypoxia and hypercapnia act on
the carotid chemoreceptors to elicit changes in autonomic
outflow to the vasculature similar to changes induced by

lowering the pressure in the carotid sinuses.

 

1‘. H
. In
R'v'uu

_H

ROLE OF THE CAROTID BODY CHEMORECEPTORS
IN THE REFLEX REGULATION OF THE

CARDIOVASCULAR SYSTEM

BY

Paul Edwin Parker

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Physiology

1972

q {I

,0?”

DEDICATION

TO MY WIFE AND PARENTS

ii

 

’:~h~

“:5. ext 3:

TIC. “fi-.
‘1. es“»a\
.15-.“ I. A;
“A‘.‘~ets \l.

 

.“

ACKNOWLEDGEMENTS

The author wishes to express his sincere appreciation
to Drs. F. J. Haddy, J. B. Scott and J. M. Dabney for their
encouragement and invaluable assistance during the course of
these investigations. The author is also indebted to the
other members of his guidance committee, Drs. W. D. Collings,
J. B. Hook and R. M. Daugherty, Jr. for their advice and
consultation. The author's gratitude is also extended to
Mr. B. T. Swindall, Mrs. J. Johnston and Mr. G. W. Gamble
whose technical assistance made this project possible.

The author wishes to acknowledge his support by the NIH

Cardiovascular Training Grant (HL 5873) during the course of

his doctoral graduate program.

 

iii

TABLE OF CONTENTS

Page
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . l

SURVEY OF THE LITERATURE . . . . . . . . . . . . .

U‘l

Anatomy . . . . . . . . . . . . . . . . . . . . . .

Physiologic Stimuli . . . . . . . . . . . . . . . .

Cardiovascular Reflexes . . . . . . . . . . . . . .
Selective chemoreceptor stimulation. . . . . . .
Changes in systemic blood gas content. . . . . . l

woooomm

METHODS O O O O O O O O O O O O O O O O O O O O O O O I 16

Perfusion of Carotid Bodies . . . . . . . . . . . . 16
Forelimb. . . . . . . . . . . . . . . . . . . . . . 21
Intestine . . . . . . . . . . . . . . . . . . . . . 23
Kidney. . . . . . . . . . . . . . . . . . . . . . . 25
Heart . . . . . . . . . . . . . . . . . . . . . . . 26
Gracilis—-Hindpaw . . . . . . . . . . . . . . . . . 28
Analysis of Samples and Treatment of Data . . . . . 30

RESULTS 0 o o I o o o o o o o o o o o o o o o o o o o o o 3.].
FOIGIiInb. o o o o o o o o o o o o o o o o o o o o o 3.1
Intestine o o o o o o o o o o o o o o o o o o o o o 41
Kidney. o o o o o o o o o o o o o o o o o o o o o o 53
Heart . . . . . . . . . . . . . . . . . . . . . . . 59
GraCiliS-—Hindpaw o o o o o o o o o o o o o o o o e 93

DISCUSSION 0 o o o o o o o o o o o o o o o o o o o o o 102

SUMMARY AND CONCLUSIONS 0 o o o o o o o o o o o o o o 0 1.1.5

BIBLIOGRAPHY o o o o o o o o o o o o o o o o o o o 0' o 118

APPENDICES
A. RAW DATA 0 o o o o o o o o o o o o o o o o o o o 125

B. STATISTICAL METHODS. . . . . . . . . . . . . . . 155

iv

 

" Average f:

receptor :
h'x'POJItic a:

0 Average fc

rece'PT-OI' :
hlpoXiC a}

I AT'I'erage VV'

intestine
With hfi'po;
and With I

Average r.

to caroti

 

 

TABLE

1-la.

2‘23.

LIST OF TABLES

Average forelimb responses to carotid chemo—
receptor stimulation by hypoxic—hypercapnic,
hypoxic and hypercapnic blood before vagotomy. .

Average forelimb responses to carotid chemo—
receptor stimulation by hypoxic-hypercapnic,
hypoxic and hypercapnic blood after vagotomy . .

Average vascular responses of ileal segment of
intestine to carotid chemoreceptor stimulation
with hypoxic-hypercapnic blood before vagotomy
and with hypoxic-hypercapnic, hypoxic and hyper-
capnic blood after vagotomy. . . . . . . . . . .

Average responses of superior mesenteric artery
to carotid chemoreceptor stimulation with
hypoxic-hypercapnic blood before vagotomy and
with hypoxic-hypercapnic, hypoxic and hypercap-
nic blood after vagotomy . . . . . . . . . .'. .

Average kidney reSponse to carotid chemoreceptor
stimulation with hypoxic-hypercapnic blood be-
fore vagotomy and with hypoxic-hypercapnic,
hypoxic and hypercapnic blood after vagotomy . .

Average reSponses of isolated hindpaw and
gracilis muscle to carotid chemoreceptor stimu-
lation with hypoxic-hypercapnic blood before and
after vagotomy . . . . . . . . . . . . . . . . .

Average hindpaw response to carotid chemo-
receptor stimulation hypoxic-hypercapnic blood
before and after vagotomy. . . . . . . . . . . .

Average hindpaw response to carotid chemo-
receptor stimulation with hypoxic-hypercapnic
blood before and after vagotomy. . . . . . . . .

Page

32

34

44

54

55

94

98

99

 

L153 3 TABLES--

 

9. Change in
ileum, ic
carotid cl'
aft r var.

 

LIST OF TABLES--Continued

TABLE Page

9. Change in vascular resistance in forelimb,
ileum, kidney and coronary vascular beds during
carotid chemoreceptor stimulation before and
after vagotomy. . . . . . . . . . . . . . . . . 103

vi

REFIESert
carotid c
h} PETS-3;:
32395.33.
CirCtlrj I
blocj I?

REPIQSE:
Carotid
CaPn c t

\8"? N ‘
I“ 936‘
'1

:71

T7
‘JPErQ

LIST OF FIGURES

FIGURE

1.

2.

10.

ll.

Carotid sinus perfusion circuit. . . . . . . . .

Representative forelimb vascular response to
carotid chemoreceptor stimulation with hypoxic—
hypercapnic blood in a vagotomized dog . . . . .

Representative forelimb vascular response to
carotid chemoreceptor stimulation with hypoxic
blood in a vagotomized dog . . . . . . . . . . .

Representative forelimb vascular reSponse to
carotid chemoreceptor stimulation with hyper-
capnic blood in a vagotomized dog. . . . . . . .

Representative vascular response of ileal seg—
ment to carotid chemoreceptor stimulation with
hypoxic-hypercapnic blood in a vagotomized dog .

Representative vascular response of ileal seg-
ment to carotid chemoreceptor stimulation with
hypoxic blood in a vagotomized dog . . . . . . .

Representative vascular reSponse of ileal seg-
ment to carotid chemoreceptor stimulation with
hypercapnic blood in a vagotomized dog . . . . .

Representative kidney response to carotid chemo-
receptor stimulation with hypoxic-hypercapnic
blood in a vagotomized dog . . . . . . . . . . .

Representative kidney response to carotid chemo—
receptor stimulation with hypoxic blood in a
vagotomized dog. . . . . . . . . . . . . . .

Representative kidney response to carotid chemo-
receptor stimulation with hypercapnic blood in a
vagotomized dog. . . . . . . . . . . . . . . . .

Average coronary vascular response to carotid

chemoreceptor stimulation with hypoxic—hypercap-
nic blood before vagotomy. . . . . . . . . . . .

vii

Page

18

38

4O

43

47

50

52

58

61

63

66

 

.z' 3? FIGL R;

21.

Average
chencrec
after \‘a

‘.
EYEIa: e
'
CT. IFS-re:

after v;

LIST or FICURES--Continued

FIGURE

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Average coronary vascular response to carotid
chemoreceptor stimulation with hypoxic-hypercap-
nic blood after vagotomy . . . . . . . . . . . .

Average coronary vascular response to carotid
chemoreceptor stimulation with hypoxic blood
after vagotomy . . . . . . . . . . . . . . . . .

Average coronary vascular response to carotid
chemoreceptor stimulation with hypercapnic blood
after vagotomy . . . . . . . . . . . . . . . . .

Representative coronary vascular response to
carotid chemoreceptor stimulation with hypoxic-
hypercapnic blood in a vagotomized dog . . . . .

Representative coronary vascular response to
carotid chemoreceptor stimulation with hypoxic-
hypercapnic blood in a vagotomized dog . . . . .

Representative coronary vascular response to
carotid chemoreceptor stimulation with hypercap-
nic blood in a vagotomized dog . . . . . . . . .

Average coronary vascular reSponse to carotid
chemoreceptor stimulation with hypoxic-hypercap-
nic blood after vagotomy . . .2. . . . . . . . .

Average coronary vascular response to carotid
chemoreceptor stimulation with hypoxic-hypercap—
nic blood after vagotomy . . . . . . . . . . . .

Average coronary vascular response to carotid
chemoreceptor stimulation with hypoxic blood
after vagotomy . . . . . . . . . . . . . . . . .

Average coronary vascular response to carotid
chemoreceptor stimulation with hypoxic blood
after vagotomy . . . . . . . . . . . . . . . . .

Average coronary vascular response to carotid

chemoreceptor stimulation with hypercapnic blood
after vagotomy . . . . . . . . . . . . . . . . .

viii

Page

68

7O

73

75

78

81

83

85

88

90

92

uni-If“
“r- \
yen...»

“Q...
tic

.F
as

\

I..- A"
..90

1"
..:.--

.9 o.--

 

LIST OF FIGURES--Continued

FIGURE

23.

24.

Page
Representative responses of isolated hindpaw
and gracilis muscle to carotid chemoreceptor
stimulation with hypoxic-hypercapnic blood in a
vagotomized dog. . . . . . . . . . . . . . . . . 96

Representative hindpaw response to carotid chemo-
receptor stimulation with hypoxic—hypercapnic
blood before and after vagotomy. . . . . . . . . 101

ix

INTRODUCTION

It is well-established that the arterial chemoreceptors
reflexly affect the respiratory system and some data are
available which suggest that they also affect the cardio-
vascular system (4). While the respiratory responses to
carotid body stimulation have been well-defined (10,11), the
cardiovascular responses have not been thoroughly investigated.
The reasons for this study were threefold. First, few studies
examining the reflex reSponses to carotid chemoreceptor
stimulation employed selective stimulation of the carotid body.
Most investigators reported the reSponses to systemic hypoxia.
Second, of the few studies in which specific chemoreceptor
stimulation was used, most were carried out employing pharma-
cologic rather than physiologic stimuli. Third, little
attention has been paid to the role of hypercapnic carotid
chemoreceptor stimulation.

The carotid body chemoreceptors are small, highly vascular
bodies located near the bifurcation of the common carotid
artery into the internal and external carotid branches. They

are sensitive to changes in the PO , PCO and pH of the
2 2

arterial blood (4). Afferent nerve fibers from the carotid

sinus and carotid body are carried in the carotid sinus nerve

 

 

:1: ‘.~'.“

0

wt: tie a

—' -u L
.

""r 1"”-

-..v6 sunerva’l-

~o..

'.‘ ‘4' e

“um“ .fi.--.L.

.
:31" .5”
‘O-vo cuU

'

':":"Hv
‘vu.h .V.
0

I “v Q“
' I‘ve-
- ult a.‘ ‘.\'.c
In.-
- FAA F ‘f‘
unu<v6tve~ 'Vrs
.

l.:‘flv

b

~W‘ec

n‘n‘.‘

“'\- V TV
A] V

t‘.‘ r:

, .
V‘ROV

tie '1':

0 A

 

 

and join the gIOSSOpharyngeal nerve. The blood vessels supply-
ing the carotid body have been shown to possess sympathetic
motor innervation (12). Activation of this innervation causes
vasoconstriction, locally regulating vascular resistance, thus
altering the volume of arterial blood flowing past the chemo-
receptors. A reduction in arterial blood oxygen tension and
pH or an increase in carbon dioxide tension stimulates the
chemoreceptors which increases the number of impulses in the
afferent nerve fibers from the carotid bodies. It has been
proposed that the increased activity in these afferent nerve
fibers stimulates the medullary vasoconstrictor center result-
ing in an increased total peripheral resistance.

Bernthal (24,28,29) studied the reflex vasomotor reSponses
in the canine forelimb and hindlimb evoked by selective carotid
chemoreceptor stimulation. These studies indicated a predomi-
nately vasoconstrictor response in both forelimb and hindlimb.
The report of increased hindlimb resistance to selective caro-
tid stimulation was confirmed recently by Pelletier (21).

A search of the literature revealed no reports of the reflex
vascular responses of other vascular beds to selective carotid
chemoreceptor stimulation.

Many investigators (40,41,42,43,44,48) reported studies on
the change in heart rate evoked by chemoreceptor stimulation,
however, the results of the studies have been extremely contro-
versialk. In animals breathing spontaneously stimulation of the

carotid chemoreceptors elicited a consistent augmentation of

 

-".‘-a.3 ‘1' rat

‘-. a‘.

.31‘ 'i.) .
.13 Lnotrc‘:
::a::"”°“tor

I
-

...~cts of Ph"
is

rather the c?
fact on tn
maintenan
tarrhage (4
‘* about 60 Ir.
Erie additic
~31 blood

9-:

ventilatory rate and depth but only slight increased or de-
creased heart rate (40,41,42). When respiration was maintained
constant by artificial ventilation the heart rate usually
diminished (43,48). In animals with controlled ventilation
pharmacologic chemoreceptor stimulation elicited bradycardia
(23,27,31).

An inotropic ventricular response to selective carotid
chemoreceptor stimulation was reported recently by several
investigators (43,48). Chemoreceptor stimulation before
vagotomy decreases ventricular contractile force. De Geest
£5 31. (48) reported that carotid chemoreceptor stimulation
produced a slight positive inotropic effect following cervical
vagotomy while Downing at 31. (43) reported a negative ino-
tropic effect.

A more thorough knowledge of the reflex cardiovascular
effects of physiologic carotid body chemoreceptor stimulation
is important for several reasons. Although it is doubtful
whether the chemoreceptor reflexes exert any significant ef-
fect on the circulation at rest they certainly contribute to
the maintenance of the cardiovascular system following
hemorrhage (4). Once the mean arterial pressure has drOpped
to about 60 mm Hg, further reduction of the pressure does not
evoke additional barostatic reflexes. However, inadequate
local blood flow to the chemoreceptors due to the low levels
of arterial pressure may produce anoxia at the chemoreceptors.

The arterial chemoreceptors are also important clinically in

 

q
.
.~lo- A‘ 1"sz
.23: u. 54;..-.
1‘ u
a, '
”u :rn . ‘
in: ion .\ o
I

' u
lAflu. ”he"? ‘L‘
fvi' yu-...,. ‘ ‘
n

.".-I". "

n.v..:‘.: ‘as:;

.I .
I'L’.‘ c¢.~_‘

ODD...“ ”v.. a
.

ego. 5‘ “0-2. .
9‘... V‘ a

UHL‘V.

LL - .
E.” NI:§ ana ”3'

I~~~ ‘.u L“
":‘he

‘u.

’nn.
a ‘ \‘:‘~ I
u.‘ “

u “"e In
..:..H‘ ‘
l:¥ : h

 

 

 

cases of cardiopulmonary diseases and especially asthma since
they are slowly adapting receptors (10).

The purpose of this study was to determine the reflex
effects of selective, physiologic stimulation of the carotid
body chemoreceptors on the forelimb, kidney, intestinal and
coronary vasculature. This selective, physiologic chemo—
receptor stimulation was accomplished by varying the gas con—
tent of autologous blood perfusing the isolated carotid
sinuses and carotid bodies by means of an extracorpeal lung
Ventilated with various 0 and CO gas mixtures. The hypothe—

2 2
sis tested in this study was: carotid body chemoreceptor stimu—

 

latipn with hypoxic, hypoxic-hypercapnic and hypercapnic blood
before and_following vagotomy evokes changes in vascular
resistance in the forelimb, intestine, kidney and coronary

vascular beds.

 

 

-‘ ‘ ‘
”A ‘ V1» ~
“W ‘I' e v --

. v ‘
’:A.A' q‘ 0-H b-
nu:ov“ v. EAL AI

is internal an

‘ “ ! 1.
:31: acres

:N

A." '
M-vo: or on t‘

“* 'OScoz:
.":., :
$.53.“ the I
:31; $-

 

 

SURVEY OF THE LITERATURE

Anatomy

The carotid body chemoreceptors are situated in the
region of the bifurcation of the common carotid arteries into
the internal and external carotid branches. In the dog the
carotid bodies are located on the root of the occipital
artery or on the common trunk of the occipital and ascending
pharyngeal arteries. The veins draining the carotid bodies
usually anastomose with the internal jugular vein (1).

De Castro (2) examined the local circulation of the carotid
body microscopically and suggested that most of the blood
perfusing the body enters sinusoids while some may be chan-
neled through arteriovenous anastomoses within the body.

The blood flow in the isolated carotid body of the cat was
found to average 40 mm3 of blood/min if blood pressure was
within the normal range (3). For a carotid body weighing 2 mg
this value represents an equivalent blood flow of about 20
Hfl/g of carotid body tissue/min. As a result of the high
\Kflume rate of blood flow through the carotid body the amount
CW oxygen removed from the blood is small. In the cat, Daly
it. Q. (3) found that at a blood flow rate of about 40 m3/

nun there was no significant arteriovenous oxygen difference

 

33255 {28 car;
Inc-‘.:oo F I. :-
:.:.-.\e He‘AU

=.~ art rial bl:

'::'\A.
s. .

~.~~..se and

GI R3. . . F
unantiflefI

”‘Itu'

“u‘v.ty of ‘3

 

across the carotid body. Thus, the blood bathing the chemo-
sensitive cells have essentially the same oxygen composition

as arterial blood.

Physiologic Stimuli

 

The carotid body chemoreceptors are stimulated by hypoxia,
increased hydrogen ion concentration and by hypercapnia,
possibly acting through changes in hydrogen ion concentration.
This will be discussed subsequently. Von Euler st 31. (4)
demonstrated the relationship between carotid chemoreceptor
response and arterial oxygen content in 1939. Hornbein 32 31.
(8) quantified this relationship by observing the electrical
activity of the carotid sinus nerve during hypoxic stimulation
of the carotid body. These and other investigators (5,6)
found the arterial oxygen-chemoreceptor response curve to be
roughly hyperbolic. The rate of carotid chemoreceptor dis-
charge increased about l.5% for each mm Hg decrease in arterial

P0 between 40 and 30 mm Hg PO (8). The sensitivity of the
2 2

chemoreceptors at high oxygen tensions was attenuated.
However, an increase in chemoreceptor discharge still occurred

'when the arterial P was reduced from 500 to 150 mm Hg (8).

O
2
While some investigators (4) related excitation of the
carotid chemoreceptors to arterial oxygen content the hypothe-
818 was challenged by the observation that a greatly reduced

oxygen content in a perfusate does not increase carotid body

 

:"‘4.' 1""
3:.l0' as V".

I d

. ,- .
”row-Z. Ff‘ A ‘ a A
voo~vu “‘V' V -uc

;::;:sal that t
flexease in ar‘
:rge: content

.azzgren and x.
L~‘q‘ “A.
.;,..e...1on gr

I: 'A a
.. .loou flow

 

 

activity as long as the O tension of the perfusing fluid was

2
adequately maintained (8). Duke gt El' (9) observed that

saturation of 70-80 percent of the blood hemoglobin with
carbon monoxide produced no carotid chemoreceptor activation
in cats. These findings supported Comroe and Schmidt's (ll)
pr0posa1 that the effective stimulus of the carotid body is a

decrease in arterial PO rather than a decrease in arterial
2

oxygen content. This concept was challenged by the work of
Landgren and Neil (7) who demonstrated that hemorrhagic
hypotension greatly increased carotid body activity. Thus,
if blood flow was markedly reduced as in hypotension the

chemoreceptors could become hypoxic even though the arterial

PO and oxygen content were normal. However, these investi—
2

gators did not monitor the blood PCO during hemorrhagic hypo-
2

tension. -Comroe (10) defined the hypoxic stimulus to the

carotid body as a decrease in the 0 supply to the chemorecep-

2
tors below that necessary for their metabolic needs.

Perfusion of the carotid bodies with blood of varying

PCO produced a somewhat sigmoid shaped chemoreceptor response
2

curve for the rate of chemoreceptor discharge when the P0 was
2

held constant at normal values (8). Several investigators

(12,13) observed.the greatest gain in the CO response curve

2
occurring over the normal range of arterial PCO , with a
2
reduction in carotid body activity at arterial PCO values
2

above 150 mm Hg. At high oxygen tensions the carotid chemo-

receptors response to CO was greatly attenuated.

2

 

 

ELISE-CI to C3“

! ' y' .
a“! ”AFN

"“- «'w3 for,
‘45 Neil (l6),

45’- ‘.he chem

 

 

Hornbein gt 21.(15) observed that in the presence of 100%

02, a C02

significant carotid chemoreceptor excitation.

tension of 150-300 mm Hg was required to yield

Although it is well-known that CO and increased hydro-

2
gen ion concentration produce carotid body excitation, much

controversy has arisen as to whether molecular CO2 has a

specific action on the chemoreceptors. Investigation of this

point is complicated by the fact when the carotid body is

. . . . +
there is a Simultaneous increase in H CO H

2 2 3'

and HCOB- formed catalytically by carbonic anhydrase. Joels

and Neil (16), and Eyzaguirre and Koyano (17) have suggested

exposed to CO

that the chemoreceptor stimulating action of hypercapnia and
increased hydrogen ion concentration are partly independent
of each other. On the other hand, other investigators
(15,18,19) have proposed that the effect of CO2 is mediated

by changes in intracellular hydrogen ion concentration rather

2. In recent work

Travis (20), employing carbonic anhydrase inhibition to delay

than by the specific action of molecular CO

the hydration of CO suggested that stimulation of the

2'

carotid body by CO is predominately through the hydrogen ion.

2

Cardiovascular Reflexes

 

Selective chemoreceptor stimulation

It is now established that the carotid body chemoreceptors

raflexlyaffect the cardiovascular system as well as

o
C
"""' non o
t:ubb v
. C

“V

U'. G-
.O'VVV

' Q . ~ '-
' n ‘ 3‘
:3: ' TH-leubJ».
k 0'
l.’ A
:..:.ac., was
- 1 FA.
ECCI‘P- by.

- ‘
géIIL'SECl Cc:

‘ I

creases in s

v 9‘ . ‘ '
.e::,ec:m e J.

“Sash by
I'I ~
,3} la a h

535113: bl:
:‘erial

.Egtlgn 1
egg 51".

respiration. Early investigations of the cardiovascular
effects of arterial chemoreceptor excitation were carried out

or high CO gases. This

by ventilating animals with low 02 2
approach was inadequate since the responses it evoked were

a complex combination of local effects on the tissues,
effects due to direct stimulation of the central nervous sys-
tem and effects due to arterial chemoreceptor stimulation.

Recently, Pelletier and Shepherd (21) subjected isolated
perfused carotid sinuses of vagotomized dogs to hypoxic,
hypoxic-hypercapnic and hypercapnic blood and observed in-
creases in systemic pressure averaging 57, 51 and 24 mm Hg,
reSpectively, for each stimulus. The mean P02 and pH values
of the blood employed to stimulate the carotid chemoreceptors
were as follows: hypoxic blood, 37 mm Hg, 7.30; hypoxic
hypercapnic blood, 42 mm Hg, 7.07; hypercapnic blood, 96 mm
Hg, 7.10.

The reflex cardiovascular effects of carotid body stimu-
lation by pharmacologic agents was studied by Heymans 33 a1.
(4) in a bilaterally isolated carotid sinus preparation with
one sinus denervated. An intracarotid injection of acidic
sodium bicarbonate (pH=7.2) produced an increase in systemic
arterial blood pressure while no effect was seen upon in-
,jection in the denervated side. Following the same procedure
using alkaline solutions produced a transient decrease in
syStemic blood prbssure. Many investigators (4,8,22,23,31)

.have employed the use of pharmacologic agents to stimulate the

 

 

:ar::'.c' CHESTCIE
n' ‘ .
..::.i:.e and c.

2:325. motor

“«|' ‘

is: in non-ya

‘
"“‘1‘V

run-ed $10.11}
C

.
‘=~d-1

4." “0:15 of

is are late

1219:1151 pres

' .
a

‘I?!
‘-

w:- b‘." be!
“Steater int

31? carotid

‘3 N- .
-Uha.“lzed

:~ \

‘fl

10

carotid chemoreceptors. Calvelo gt a1. (23) employed
nicotine and cyanide to stimulate the bilaterally isolated
carotid chemoreceptors in the dog. Their findings indicated
that in non-vagotomized animals, injections of nicotine
produced significant decreases in systemic arterial pressure.
Injections of cyanide produced decreases in pressure in some
experiments and increases in others. A subsequent study from
the same laboratory (46) reported an increased systemic
arterial pressure resulting from carotid chemoreceptor stimu-
lation by both nicotine and cyanide in non-vagotomized dogs.
A greater increase in systemic pressure was observed follow-
ing carotid body stimulation in vagotomized dogs.

Bernthal 33 31. (24,28,29) studied the reflex vasomotor
responses in canine forelimbs and hindlimbs evoked by chemo-
receptor stimulation. Vasomotor activity was assessed in
vagotomized dogs by observing changes in blood flow in the
axillary artery by means of a thermo-electric method by Bronk.
The preparation consisted of a bilaterally isolated, perfused
carotid sinus circuit containing a reservoir to prevent
reinfusion of the hypoxic blood perfusate. Perfusion of the
sinuses with anoxic blood produced axillary vasoconstriction
'wtflch became maximal in about 30 seconds. Reflex responses
(would not be elicited with blood equilibrated with more than
115%s02. Similarly, Winder et_al. (25) showed stagnant anoxia

i1: the carotid body to evoke reflex vasoconstriction in fore-

liflMb‘vessels.

 

 

 

 

Rule tot

waJA.‘ n It
.UIUb—A‘Al .0

'II

. q 1 _
.25, (users:
I Q ‘
3:23:31 m1; c-

mum-

.DU:VObbeS 1n t
. carotid br
Intracaroqd ~
IIQ'A:- o
““"c“=es 1“
"Al:

“June or C“

Si: hr ‘ I
’1 wessne

.—
:1
a:
*1
(D
7

‘03 0f ti‘e -
”‘rcapnic ~

'55 n
“:SQS
\ of t
MECti.

(

 

11

While total limb vascular resistance appears to indicate
a predominant vasoconstrictor response in forelimbs and hind-
limbs, observations on the individual responses of the
skeletal muscle and skin vascular beds are in need of further
investigation. Calvelo gg g1. (23) observed the vasomotor
responses in the gracilis muscle and paw of the hindlimb dur-
ing carotid body stimulation with nicotine and cyanide.
Intracarotid injections of either nicotine or cyanide caused
increases in gracilis muscle perfusion pressure. Neither
nicotine or cyanide caused significant changes in paw perfu-
sion pressure. More consistent reductions in paw perfusion
pressure were observed with pharmacologic chemoreceptor stimu—
lation following phentolamine.

In a recent study by Pelletier and Shepherd (21) the
response of the perfused hindlimb was observed during perfu-
sion of the isolated carotid sinuses with hypoxic, hypoxic
hypercapnic and hypercapnic blood. External iliac artery
perfusion pressure increased 58 mm Hg during the hypoxic
stimulus, 59 mm Hg during the hypoxic hypercapnic stimulus,
and 31 mm Hg during the hypercapnic stimulus to the carotid
chemoreceptors.

While a few studies have reported the effects of sys-
temic hypoxia on the intestinal (24,47) and renal (32,33,34)
vasculatures, no studies have been carried out in which re-
sponses of the intestine and kidney were observed during

selective stimulation of the carotid chemoreceptors.

 

Several :

:‘ections cf

reactor stir,

2;: the tack:
:Liztures is r.
with SOlUtior.
ma: . ,

vuu‘a unrlng
if the

IESpi:

.n ex;er he“

 

tzl*vt'lon wer
I‘BI

\
F s
N. (”5”
“:3. has
A
C
‘~::
C

12

Several investigators (23,27,31,46) reported that local
injections of cyanide and nicotine into the carotid sinus
circulation caused bradycardia. Other investigators (35,36,
37,38) observed reflex tachycardia to result from chemo—
receptor stimulation by systemic anoxia. The experiments of
several investigators (39,40,4l,42,43) suggest that, in the

dog, the tachycardia resulting from breathing low 0 gas

2
mixtures is not primarily a result of arterial chemoreceptor
stimulation. Bernthal g5 g1. (39) perfused the carotid sinuses
with solutions of low 02 content and observed a slight brady-
cardia during hypoxic stimulation which became more pronounced
if the respiration was controlled by artificial ventilation.

In experiments in animals with controlled ventilation where

the isolated carotid sinuses were perfused with hypoxic blood,
bradycardia, a reduced cardiac output and systemic vasocon-
striction were observed (40,41,42,43). Allowing the animals

to breathe spontaneously during carotid chemoreceptor perfu-
sion with hypoxic blood produced variable responses with the
heart rate remaining unchanged, increasing or decreasing (40,
41,42).

Although several investigators have determined the effects
of chemoreceptor stimulation on the heart rate, there is little
information concerning the effects of carotid chemoreceptor
stimulation on the myocardium and coronary vascular resistance.

In dogs having controlled respiration, Downing gg_gl. (43)

found that hypoxic stimulation of the isolated carotid sinuses

'......; g“ “
..‘-.X-a ‘A. .4
..

i.e_:t the left

n
‘xw-n e .. -
."'-” Loom
‘ a

 

- 7“
“" cechI

:u- a“ n ‘.

N.- dint-afar.

‘«

.....l and CC

.L:

h.»

s'.
‘s Q n
~5rs in t‘ ‘
A
no
tiah.‘

13

produced a reduction of ventricular contractility. De Geest
2E.E£° (48) observed a similar negative inotropic effect of
hypoxia in an isolated carotid sinus on a preparation which
kept the left ventricle isovolumetric. After vagotomy a
slight increase in ventricular performance was evoked, sug-
gesting that the primary reflex cardiac effect of carotid
chemoreceptor stimulation is to increase vagal tone. Stern
and Rapaport (44) reported an increase in myocardial contrac-
tility and coronary vasodilation resulting from activation of
the aortic chemoreceptors. Studies by Vatner gg‘gl. (45) have
shown that direct stimulation of the carotid sinus-nerve
caused coronary vasodilation in conscious dogs which was at-
tributed to a reduction of sympathetic tone. Recently,
Hackett 33.31. (46) have demonstrated that stimulation of the
isolated carotid bodies by nicotine and cyanide produced,
reflexly, coronary vasodilation by activation of cholinergic

fibers in the vagus.

 

ighanges in systemic blood gas gontent

Early studies of the cardiovascular responses to chemo-
receptor stimulation were performed by Heymans 22.3l' (4).
These investigators observed that acute hypoxia induced by
nitrogen inhalation produced systemic hypertension only if the
sinoaortic nerves were intact. If respiration was maintained
constant by artificial ventilation the inhalation of the low
0 gas mixture usually produced only a decrease in systemic

2
pressure after section of the sinoaortic nerves (4,47).

 

7. 5 In
L“ Lost

.

I.:--~ J to ‘l

enulbvd J v n

- 0-. '

P‘.n f-“ ".-

an..-wa ..-
“hh”. ‘ l... _

htnvounu‘. \rv.

-. q. .- &‘u- .
‘L ‘nn‘..es -‘le ‘

“the; .
~y~~h‘Ey-‘fi
5v
Q a .
ht¥a=e l
n T7:
i-Qv ‘
.l..e the
OK» ar-
\
FE‘
h.
w\.'\
s
I.

‘-
_~
K‘VTIQ‘.’
' "51C C‘
k ,
fl
5““
’ {,EH+~ .
“\.‘
i.
‘4‘ ya u
“8\
«8+-
Car-
=q'
‘ql‘.

V 3 .
MN
H‘l
Q
“
‘yip.
\
e
~e cs
vL
,
A
~=ET~

14

In the limb Litwin g2 g1. (30) reported systemic anoxia

induced by 5% 0 caused vasoconstriction in the perfused

2
hindlimb. Korner and Uther (26) reported a study employing
a thermal conductivity method for estimating skin blood flow
in unanesthetized rabbits which indicated that systemic
hypoxia decreased cutaneous vascular tone and increased
vascular tone in muscle.

Bernthal and Schwind (24) compared the reflex vasocon-
strictor responses in the limb vasculature with those of the
intestine during systemic hypoxia. The inhalation of 10% O2
in nitrogen produced vasoconstruction in the intestinal
vasculature which reduced the blood flow in the superior
mesenteric artery by 65%. The same stimulus produced a de-
crease in mesenteric artery blood flow of 31% in a preparation
where the aortic depressor nerves were cold blocked. The
reflex response of the superior mesenteric artery to arterial
hypoxia was also examined by Krasney (47) using an electro-
magnetic flowmeter. Under conditions of spontaneous respira-
tion, ventilation with 6% O2 - 94% N2 evoked a marked increase
in resistance in the superior mesenteric artery. When the
animals were thoracotomized and artificially ventilated,
arterial hypoxia produced a smaller increase in resistance in
the superior mesenteric artery.

Studies which have attempted to examine the reflex re-

sponse of the kidney to chemoreceptor stimulation have only

been carried out using systemic hypoxia. Caldwell gg g1. (32)

 

1 ‘

A.~-~ A“
vlovec J ¢
"5?» av- C
........ :1 -

‘ 1 e
"7"" n h .
e...‘_e‘ ~37 c

15

reported that moderate arterial hypoxia in man and the dog
produced only minor reductions in renal blood flow and
glomerular filtration rate. Franklin 23.3l' (33) observed
marked reductions in renal blood flow during systemic anoxia
induced by asphyxia.

Korner (34) reported that exposing unanesthetized rab-
bits to 9.6% O in N2 or CO produced renal vasoconstriction.

2
He observed that a greater reduction in arterial P0 was

necessary to increase respiration. Denervation of Ehe carotid
sinus region and depressor nerves during hypoxia resulted in
a decrease in renal vascular resistance, and subsequent ex-
posures to hypoxia had little effect upon renal blood flow.
Although the literature reports various attempts by many
investigators to elucidate the reflex reSponses to carotid
chemoreceptor stimulation, few studies have been carried out
in which the chemoreceptors were stimulated Specifically. Of
the few studies in which specific chemoreceptor stimulation
was used, most were carried out employing pharmacologic rather
than physiologic stimuli for the chemoreceptors. Little at-
tention has been paid to the role of hypercapnia in reflex
responses elicited by carotid chemoreceptor stimulation. In
view of the inadequate knowledge in this area, the purpose of
this investigation was to examine the reflex responses of the
forelimb, hindlimb, kidney, intestine and coronary vasculature

to selective physiologic stimulation of the carotid body

chemoreceptors.

Mongrel dogs
aesthetized with
texzsly. Respir

gressure respir at

an
\\

...I. In the tj

I:

gassively during ‘

:: wa‘e'

to prove:

rsrrzred surge ry.

5m, 5 rug/kg.
2.:32‘ pressures IT.

Line displaceme

lines, model P23

.‘ o
n.“
‘3‘. l

nto a dire

Iiel 7796A, Wait

The carotid
Mflied bilate

r‘f

 

. Ceptor in:

“vial. ascendir.

(its: ‘
31 arteries

 

METHODS

Mongrel dogs of either sex weighing 15-20 kg were
anesthetized with sodium pentobarbital, 30 mg/kg, given intra-
venously. Respiration was maintained constant by a positive
pressure respirator (Harvard Apparatus Co., model 607, Dover,
Mass.). In the thoracotomized animals the lungs collapsed
passively during expiration against a resistance of 2-2% cm
of water to prevent atelectasis. Following completion of the
required surgery, the animals were treated with heparin
sodium, 5 mg/kg, to prevent blood coagulation. All of the
blood pressures monitored were continuously recorded by low
volume displacement pressure transducers (Statham Labora-
tories, model PZBGb, Hato Rey, Puerto Rico) which provided
imput into a direct writing oscillograph (Hewlett-Packard Co.,

model 7796A, Waltham, Mass.).

Perfusion of Carotid Bodies

The carotid sinuses and carotid bodies were surgically
isolated bilaterally, taking care not to damage the carotid
chemoreceptor innervation. The internal carotid, laryngeal,
lingual, ascending pharyngeal, occipital and any other col-

lateral arteries were ligated bilaterally. The internal

16

3:15 arte‘fl’ wa:
re:e;:or and the I
was ligated dist

Perf‘ ion of
225125 was provid
al‘n; removed fr
sari: was admin
is left lung was
5:22 intercosta
:f the experiment

5553. Middleport

I

steal long. '1

..~
.3.)

“Estonia tied ir

s'"

.

.H ".V
'ude

19d at a cc

SE The outi
IS" a“ (”Teen e2

3255: .
4 Oxigen mac

I

:30: Calif.) aTIC

R.‘

-41. The Sinus

3: p .
Sit .

“’1 Periods 1
510';

cannula . T}

Orporeal ll

l
u ."
.luac

D
H

‘3» r -
.6813tanCe

I33

y

17

carotid artery was ligated distal to the carotid sinus baro-
receptor and the occipital and ascending pharyngeal arteries
were ligated distal to the carotid body.

Perfusion of the isolated carotid sinuses and carotid
bodies was provided by an extracorporeal circuit containing
a lung removed from another dog (Figure 1). Prior to surgery
heparin was administered to the animal donating the lung and
the left lung was removed through an incision in the left
fourth intercostal Space. Blood from the left femoral artery
of the experimental animal was pumped (Sigmamotor Inc., model
T-GSH, Middleport, N. Y.) into the pulmonary artery of the
isolated lung. The venous blood from this lung flowed through
a cannula tied in the partially preserved left atrium and was
delivered at a constant rate to the isolated carotid sinuses
and bodies by a second blood pump (Sigmamotor Inc., model
T-GSH). The outflowing blood from the carotid sinuses flowed
past an oxygen electrode (Beckman Instruments, Inc., model
325814 oxygen macroelectrode, model 160 gas analyzer, Palo
Alto, Calif.) and returned to the animal via the left jugular
vein. The sinus perfusion pressure was maintained constant
and approximately equal to that of aortic pressure during the
control periods by adjusting a screw clamp on the sinus out-
flow cannula. The blood flow rate of the second pump in the
extracorporeal lung perfusion circuit was fixed and the out-
flow resistance was adjusted such that the perfusion pressure

was approximately equal to the aortic pressure. The pump flow

.ufisouwo SOHm5muom modem oHuoumu .H ousmwm

 

18

 

23> 53:03..
O...

.530 umammmEJb umammmma

. immom 9:th 33.150
’ I I I
4

                 

 

  

 

zmeoud
- u «on. w
e .. aroma
/ 923
A I I k rmmammuE E2;
215 o..-bm<o I <c§w
553$ ESSEX ¢
I .2252»;
uSmmmE
4 E l .3...
‘ ‘ I
v EEEXX

9556 5328
Eur: Eco—am...
scan I.

 

 

maintained at
5125 rate of the

fixated, as nece

 

I
:z'ewithin the J
555:3. Both pulrh

|
Latezi lung were r
Byteszic arterial
Leg-11a in the le

1%?61 of the aort

 

3’55 continuoIJsly

“o

Vernal carotid

The isolate-c

we b100d Dc:
3131' 1-

19

was maintained at this rate throughout the experiment. The
flow rate of the first pump in the perfusion circuit was
adjusted, as necessary, to maintain the pulmonary vein pres-
sure within the physiological range to prevent pulmonary
edema. Both pulmonary artery and vein pressures of the iso-
lated lung were measured throughout the experimental procedure.
Systemic arterial pressure was continuously monitored from a
cannula in the left common carotid that was advanced to the
level of the aortic arch. Unilateral carotid sinus pressure
was continuously measured from either a cannula in the left
internal carotid artery or a cannula in the left external
carotid artery advanced to the level of the carotid sinus.
The isolated lung was ventilated with a stroke volume of
300-400 ml at a rate of lG/min which insured rapid equili-
bration of the blood perfusing the isolated lung with the
ventilatory gas mixture. The isolated lung was ventilated
with gas mixtures designed to maintain the gas content of the
blood normal or render it hypoxic, hypoxic-hypercapnic or
hypercapnic. The ventilatory period for a particular gas
ndxture was terminated when the monitored pressures had
:reached steady-state values, which usually took 3 to 4 minutes.
{the systemic arterial pressure, carotid sinus pressure and
arterial perfusion pressure of the vascular bed under study
were continuously measured throughout the experiment. The pH
of the blood perfusing the carotid sinuses was measured just

prior to termination of the ventilatory period. The blood

szgles for pH detv
:: a tracorporeal
;;';w:r.a:y outflow 3

To change the
:lcciperfusing th-
anlated with va
222:3: gas mixtur
iz' 2‘." C02. The
3% :32 was 917191031—
:e‘swhile the cor.

£51595. in 51.11388"

-13’entilation of
.:"I;

\‘tA.:Ig 0% O -

‘ 2 2.
J" .

...1031w1th a Gas

3:5
...c blood was :h

23‘! .
mag 20% O . ’I

 

20

samples for pH determinations were drawn anaerobically from

the extracorporeal lung circuit between the lung and the

pulmonary outflow pump.

To change the oxygen and carbon dioxide content of the
blood perfusing the carotid bodies the isolated lung was

ventilated with various O2 and CO2 gas mixtures in N2. The

control gas mixture contained either 20% O2 - 5% CO2 or 20%

O - 2%% CO The control gas mixture containing 20% O2 -

2 2'

5% CO2 was employed during the study on the forelimb vascular

beds while the control mixture containing 20% O2 - 2%% CO2

was used in subsequent studies. Combined hypoxia and hyper-
capnia were produced in the blood perfusing the carotid bodies
by ventilation of the isolated lung with a gas mixture con-

taining 0% O2 - 20% C02. Hypoxic blood was produced by venti-

lation with a gas mixture containing 0% O2 - 5% C02. Hyper-

capnic blood was achieved by ventilation with a mixture con-
taining 20% O2 - 20% C02.
In an additional study on the coronary vasculature graded

changes in P and pH of the perfusing blood were accomplished

O2

jby'employing additional gas mixtures. In this group of
animals different levels of hypoxia were produced by ventilat-
i439 the extracorporeal lung with gas mixtures containing 5%

02 - 2&4 CO2 and 10% O2 - 2&3 C02. Hypoxic—hypercapnia was

Produced by ventilation with 10% O2 - 10% CO2 while hypercapnia

alone was achieved by ventilation with 20% 0:2 - 10% C02.

i" gas mixtures e
satiari grade.

The use of th
:a;'.:' changes in l
:iages in system
arzerzal blood dur
ration with varic
med no alterat;
As a check f '

2 respiratory mr'

..e::receptor sti:

“LAW
wakes emplo>7ed
vases and bodie

’~ lie chemorece:

m

‘0 StUdY the
2:5. .

uremb vascx;

it.

I. ~EP

'A
D

N” ~‘gg was Circ

0“
.
‘N '1?\ I

menial art;

 

~'..L:Lb neIVes "I

21

All gas mixtures employed in the above studies were certified
standard grade.

The use of the extracorporeal lung circuit permitted
rapid changes in local blood gas content without detectable
changes in systemic blood gas content. Samplings of systemic
arterial blood during ventilation of this isolated lung prep-
aration with various hypoxic and hypercapnic gas mixtures
showed no alteration of systemic blood P02, PCO2 of pH (64).

As a check for chemoreceptor stimulation, the changes
in respiratory movements produced by hypoxic-hypercapnic
chemoreceptor stimulation before vagotomy were monitored by
pneumograph or by observation. Increased respiratory move-
ments during stimulation suggested that the surgical pro-

cedures employed for isolation and perfusion of the carotid

sinuses and bodies had not greatly affected the innervation

of the chemoreceptors.

Forelimb

 

To study the reflex effects of carotid body stimulation
cu1forelimb vascular resistance the innervated, collateral
free forelimb of 13 dogs was perfused through the brachial
artery at constant flow. The skin of the right forelimb of
the dog was circumferentially sectioned 3-5 cm above the elbow.
The huechial artery, the brachial and cephalic veins and the

forfilimb nerves were isolated and the remaining muscles and

::r:.e::ive tissue

mite right “5
.zszeasured lugt
netrachial art-C”
::a:':ial artery a:
racial and C91!er
tar, radial and
:ated with an ifu
Taebrachial and
3-5 cz- above the
taxi-lated with a
3211;. The outfl;
resemir mainta;
~ (Sigmamotor
£1335 to the am:
Met

ermined h

LII

4‘ In

E‘s”
“‘“aat
Ory Periq

 

 

22

connective tissue sectioned by electro-cautery. Following

the administration of heparin, a blood Rump (Sigmamotor Inc.,
model T-6SH) was interposed between the right femoral artery
and the right brachial artery. Forelimb perfusion pressure
was measured just proximal to the point of cannulation of

the brachial artery. Blood entered the limb only through the
brachial artery and returned from the limb through the
brachial and cephalic veins. The forelimb nerves (median,
ulnar, radial and musculocutaneous) were left intact and were
coated with an inert silicone solution to prevent drying.

The brachial and cephalic veins were partially transected

3-5 cm above the elbow and the distal end of each vessel was
cannulated with a short section of polyethylene tubing (P.E.
320). The outflow from both veins was directed into a
reservoir maintained at constant volume with a variable speed
pump (Sigmamotor Inc., T-6SH) which continuously returned
blood to the animal via a cannulated jugular vein. Blood flow
was determined by timed collections of the brachial and cep-
halic venous outflows just prior to the termination of a
ventilatory period. In the dog forelimb the median cubital
‘vein represents the major anastomotic channel between the
brachial and cephalic veins. This vessel was ligated in all
experiments so that the brachial venous flow was predominately
fromlnmscle whereas cephalic flow was predominately from skin.
‘AlthCMgh this approach does not accomplish complete functional

iSOl-a'tion of skin and muscle blood flows, the degree of

aeration lS SUI.

1112325 in the tw

   

:::;I::eal lung Wi‘!
lie: the monitore'
catalic vein out.
Extermination '
sins perfusion c
uzraccrporeal l;
"T202 - 5% C02).
332) and hyperca;
ieuonitored pral
E‘-l:z.".ation the cl
5%! ieterminatior'
tinted t0 the cor|

L

«Ed samplings ~.

‘3: .
.9 bilaterally
Stabiv' .

ted wlth i

 

320.3% - I
cording+

 

To
Study th

L.
\‘y

I-.1
\i,

23

separation is sufficient to permit comparison of resistance
changes in the two parallel coupled beds (68).
The experimental protocol was to ventilate the extra-

corporeal lung with the control gas mixture (20% O - 5% C02).

2
When the monitored pressures had stabilized, brachial and
cephalic vein outflows were measured and a blood sample for

pH determination was drawn anaerobically from the carotid
sinus perfusion circuit. After the initial control period the
extracorporeal lung was ventilated randomly with the hypoxic

(0% O - 5% C02), combined hypoxic-hypercapnic (0% O - 20%

2 2

C02) and hypercapnic (20% O2 - 20% C02) gas mixtures. When
the monitored pressures had stabilized during chemoreceptor
stimulation the outflows were again measured, blood was drawn
for determination of pH and the extracorporeal lung was re-
turned to the control gas mixture. Following stabilization
during the control period, the blood flow measurements and
blood samplings were repeated. At this point the animals
were bilaterally vagotomized at the cervical level. Upon
stabilization, the carotid chemoreceptors were again randomly

stimulated with hypoxic, hypoxic-hypercapnic and hypercapnic

blood according to the procedure described above.

Intestine

 

To study the reflex effects of carotid body chemoreceptor

Stimulation on intestinal vascular resistance, an isolated

55.19:: of ileum '»
a::::stant flow .
zlength was ex:-
:=.'e to minimize

star; to this 55

4-4. single a:
guided by cam-..
93512? a blood 9
H.) between ti.
552m. PerquLI
issued throuoh
'4‘»: the output t,
Section were lef.

33' n

I
L)
0"
m
:J
rf
H
’r
J
{D
Q;
r- F)
—— i — — — —'

55
'd; h
eKHQSed thr
h: h
.. are

 

 

24

segment of ileum was perfused through a mesenteric artery
at constant flow in 9 animals. A section of ileum 15-20 cm
in length was exteriorized through a midline incision. Taking
care to minimize damage to extrinsic nerves, the single large
artery to this section of ileum was dissected free, the col-
laterals ligated and the mesentery cut on both sides of the
section so that all arterial flow to the section was carried
by this single artery. Blood flow to the isolated section was
provided by cannulating the distal end of the artery, inter-
posing a blood pump (Sigmamotor Inc., model TMlO, Middleport,
N. Y.) between the right femoral artery and the artery to the
segment. Perfusion pressure of the isolated section was
measured through a 22 gauge needle tipped cannula inserted
into the output tubing of the pump. The veins from the ileal
section were left intact. Occlusive ligatures of heavy cord
were placed at each end of the ileal section under study.
An open tipped cannula was inserted into the saline filled
lumen of the section to Monitor intraluminal pressure. After
all operative procedures were completed the section of
intestine was moistened with saline and covered with a sheet
of celloPhane to prevent drying. A heat lamp was used to
Inaintain the segment at near body temperature.

In four animals the superior mesenteric artery was per-
fused at constant blood 'flow. The superior mesenteric artery
was exposed through a midline abdominal incision. The artery

was <3arefully dissected free and cannulated distally with a

.....‘.~ 1
.z....::S 8298; C-

mesenter.

. .
..c'. .v. “
a

.I'“- ‘ .
‘ ‘~~A.Cr AnCOI

'.-a.«.~>v b
.

”awe was uni

uvv~ bio.

I :‘I v .“
5' .s‘le prC'Cea-A

‘
"woo

I i '
:v.‘ AIQ'are; k'l'h

3.. your».

:fl‘; A . a
.0'.‘ th nainta‘r‘a

.
; :eot t" "
. LVL

filmed in this

is exceptions 1:
"1.313395 contain
ilPZXlC- ypercapr
listed before \'

753333 outflow.

To study it
Ezrenal vascul:
:SIStant blood :'
35%" retr0peri':

iii-hilly to VlS'-

 

L1,
‘J‘Cd I. ,

-” mp (Sic;
“he" the right

"is perfUSIOn r“

 

25

stainless steel cannula. Blood flow to the cannulated
superior mesenteric artery was maintained constant by a pump
(Sigmamotor Inc., model T-6SH). The venous outflow from the
intestine was undisturbed. Following completion of all
operative procedures the intestine was moistened with saline
and covered with cellOphane to prevent drying. A heat lamp was
used to maintain the area at near body temperature.

Except for minor differences the experimental protocol
followed in this study was the same as that for the forelimb.
The exceptions in this study were: 1) the control gas mixture
— 2% co

employed contained 20% O 2) only the combined

2
hypoxic-hypercapnic (0% O

2,
2 - 20% C02) gas mixture was admin-
istered before vagotomy, and 3) there were no measurements of

venous outflow.

Kidney

To study the reflex effects of carotid body stimulation
on renal vascular resistance the left kidney was perfused at
constant blood flow in 10 animals. The left kidney was ex—
Posed retrOperitoneally through a flank incision and retracted
medially to visualize the renal artery. Following the admin-
iStration of heparin the renal artery was cannulated and a
-blood pump (Sigmamotor Inc., model T-6SH) was interposed be-

tween the right femoral artery and the left renal artery.

f”lee perfusion rate of the renal artery was initially set so as

:grci‘xe a perf‘
5:25 gressure as
:a'siirey.

The experirre:
are as that for
jrriac' the extra:
:3pcxic-hypercagr.
1'31 gas. The a:.

slated l

ung wit
axis gases.

To study thfi.
3:. renal vascula:

:9 was used.

2:9:
““59 the Out:

 

fin"
{if
(“f
I:
n)
(I)
(D
X
T)
O
U)
m
——’—— ——

 

 

26

to produce a perfusion pressure as close to aortic and carotid
sinus pressure as possible while maintaining the viability of
the kidney.

The experimental protocol followed in this study was the
same as that for the intestine. Following an initial control
period the extracorporeal lung was ventilated with the
hypoxic-hypercapnic gas mixture and then returned to the con-
trol gas. The animals were then vagotomized and the procedure
repeated after a control period by randomly ventilating the
isolated lung with the hypoxic, hypoxic-hypercapnic and hyper-
capnic gases.

To study the reflex effects of carotid sinus hypotension
on renal vascular resistance the kidney preparation employed
above was used. Carotid sinus pressure was reduced by de-

creasing the outflow resistance of the sinus perfusion circuit.

Heart

To study the reflex effects of carotid body stimulation
(nicoronary vascular resistance the left common coronary
artery was perfused at constant blood flow in 10 dogs. The
heart was exposed through the left third intercostal Space
and a suture was passed around the left common coronary artery
at the junction of the artery with the aorta. The animal was
heparinized and the input tubing to the pump (Sigmamotor Inc.,

moCiel T-GSH) inserted into the right femoral artery and filled

enticed. A CU:
site internal d:
as attached to ti
at: the left sub<
agblood, the ca:
aria into the mo
ted in place. T
axially set so
tier-tic and car
taining the viabi.
ifthe coronary a
tipped cannula i:
hf: ventricular
52a111961199 arc:
Tiarleston, s, C
:1“ Contractil‘
mesIECtion o
Ezi’erillental per
Change in contra

The eXperirl
is the Same as
tries of heart

ii! 1
why dEViat;

 

'v
“‘8‘

“hat gas 111*

 

hiter

2h
1 €02 0r 5% or

27

with blood. A curved metal cannula of about the same diameter
as the internal diameter of the left common coronary artery
was attached to the output tubing of the pump and inserted
into the left subclavian artery. While the pump was deliver-
ing blood, the cannula tip was manipulated down the ascending
aorta into the mouth of the left common coronary artery and
tied in place. The perfusion rate of the coronary artery was
initially set so as to produce a perfusion pressure as close
to aortic and carotid sinus pressure as possible while main-
taining the viability of the heart. The perfusion pressure
of the coronary artery was measured with a 22 gauge needle
tipped cannula inserted into the output tubing of the pump.
Left ventricular contractile force was measured with a 120 ohm
strain gauge arch (James L. Butterfield, P. O. Box 412,
Charleston, 8. C.) sutured to the surface of the left ventri-
cle. Contractile force was assessed by measuring (in mm) the
pen deflection on the recorded tracing during the control and
experimental periods. The data were reported as the percent
change in contractile force during the experimental maneuvers.
The experimental protocol followed in the heart studies
was the same as that for the intestine and kidney. A second
Series of heart studies was carried out in 6 animals in which
the only deviations from the previously described protocol
were that gas mixtures containing 10% O - 10% CO (hypoxic-

2 2

hYipercapnia), 20% O2 - 10% CO2 (hypercapnia) and 10% O2 -

zfih CO or 5% O - 2%% CO (hypoxia) were substituted for the

2 2 2

A 2 '
III-man “5‘3“

1121285-

F."

:0 further ‘3
s::.';1ation on r

skeletal muscle ‘

E

 

V1; A '6‘.
~~ali 3.

““ng with 1
are ligated. H'
each end of the

Theob

turator ne

h ”H
,:::.sed at cons
.3432“

, anotor Inc
133 the gracili
‘35 initially s
33Xinately eqt

The skin c

“Yes Were 18
-.}Sr~‘
~98 sect;

28

previously used 20% O2 - 20% CO2 and 0% O2 - 5% CO2 gas

mixtures.

Gracilis--Hindpaw

 

To further delineate the reflex effects of carotid body
stimulation on resistance to blood flow through skin and
skeletal muscle an isolated skin, skeletal muscle preparation
was employed. The right gracilis muscle was exposed and dis-
sected free from connective tissue. All blood vessels com-
municating with the gracilis except the major artery and vein
were ligated. Heavy cord occlusive ligatures were placed at
each end of the muscle to eliminate collateral blood flow.

The obturator nerve remained intact. The gracilis muscle was
perfused at constant flow by interposing a blood pump
(Sigmamotor Inc., model TMlO) between the right femoral artery
and the gracilis artery. The perfusion rate of the gracilis
was initially set so as to produce a perfusion pressure ap—
proximately equal to systemic and carotid sinus pressure.

The skin of the right hindpaw was circumferentially
sectioned 3-5 cm above the tarsus. The right cranial tibial
artery, right superficial branch of the cranial tibial artery,
Plantar and dorsal branches of the saphenous vein and hindpaw
nerves were isolated and the remaining connective tissue and
muscles sectioned by electro-cautery. The tibia and fibula

Were cut and the ends of the marrow cavities packed with bone

ax. Blood enter
may and superf
Tze hindpaw nerV-‘i
fiular) were lei
tray to prevent
assistant flow
rial T3410) whic.
2:st to a Y-cai
the tibial arter
ti tibial arter
tantala inserted
:15 Preparation
iii muscle blood

Reflex eff.I

it‘i‘lied in 3 anil

 

 

29

wax. Blood entered the paw only through the cranial tibial
artery and superficial branch of the cranial tibial artery.
The hindpaw nerves (tibial, saphenous, superficial and deep
fibular) were left intact and coated with an inert silicone
spray to prevent drying. The tibial arteries were perfused

at constant flow by a second blood pump (Sigmamotor Inc.,
model TMlO) which delivered blood from the right femoral
artery to a Y-cannula which allowed simultaneous perfusion of
the tibial arteries. The perfusion pressure of the gracilis
and tibial arteries were measured via a 22 gauge needle tipped
cannula inserted into the output tubing of the perfusion pumps.
This preparation permitted almost complete separation of skin
and muscle blood flow (68).

Reflex effects of chemoreceptor stimulation in skin were
studied in 3 animals. In these animals the skin of the right
hindpaw was circumferentially sectioned 3-5 cm above the
tarsus. The right cranial tibial artery and the superficial
branch of the cranial tibial artery were isolated and perfused
by means of the perfusion circuit described above. In these
experiments the collateral flow to the paw was not disturbed.

Finally, in 2 animals the skin of the paw remained in-
tact and the right cranial tibial artery was isolated through
a small longitudinal incision in the skin. The cranial tibial
artery was then perfused by means of a blood pump (Sigmamotor
Inc., Model TMlO) which diverted blood from the right femoral

artery.

The experire
Stuiies was ident
Theorotocol dif‘

assure and kid

.32 "o ) and
. ‘ 2 ‘

ares wer e used

:s following V3:

Anale
N-

The pH dete
with an expanded
Inc., model 22,
ticns were made

.s;.icates. P \

4.435“. (69) '

 

 

30

The experimental protocol followed in the hindlimb
studies was identical for each of the 3 series of experiments.
The protocol differed from that employed in the forelimb,
intestine and kidney studies in that only the control (20% O

2

- 2%% C02) and hypoxic-hypercapnic (0% O — 20% C02) gas mix-

2
tures were used to ventilate the extracorporeal lung before

the following vagotomy.

Analysis of Samples and Treatment of Data

The pH determinations from blood samples were measured
with an expanded scale microelectrode pH meter (Radiometer
Inc., model 22, COpenhagen, Denmark). Statistical evalua-
tions were made using the Student t—test modified for paired
replicates. P values less than 0.05 were considered sig—

nificant (69).

i'terial Pressu:
in: With 0% 0
' 2
he averag;
the carotid Sir.

‘Io,P '

,nic bio
Significant inc:

3325 EXDer
t s

imEnt

 

V

.‘k‘n

RESULTS

Forelimb

 

The average responses of the forelimb, systemic blood
pressure and heart rate to perfusion of the isolated carotid
sinus regions with hypoxic, hypoxic-hypercapnic and hypercap-
nic blood before vagotomy are shown in Table l. The only
significant response observed was an increase in systemic

arterial pressure during ventilation of the extracorporeal

lung with 0% O2 - 20% C02.

The average responses of the forelimb to perfusion of
the carotid sinuses with hypoxic, hypoxic-hypercapnic and
hypercapnic blood following vagotomy are shown in Table 2.
Significant increases in systemic arterial and brachial
artery perfusion pressure occurred during ventilation with
each experimental gas. Systemic arterial pressure increased
to a greater extent (31%) during hypoxic-hypercapnia than
during hypoxia alone (14%) or hypercapnia alone (15%).
Brachial artery perfusion pressure also increased to a greater
extent (18%) during hypoxic-hypercapnia than during hypoxia '
alone (9%) or hypercapnia alone (11%). There were no sig-
nificant changes in brachail or cephalic vein outflows indi-

catfiing that the changes in resistance were comparable in both

31

 

 

. Cfl:~\NE
0m fl 30H“ U004n xhwUHn HQflfiUQNn cam: oHOHUCOU " «U» owumh “Hum: n m: omuzm
[23%; >LCJH3 HQ_£UQL2 i <2; .3L3meLQ QSCflm UHuOHQU H WUQ oQMZEQQHQ Nfiflhgwhm

1v fl—-.I...,d :\r: .t mu . o >...nqun.v~u-vv> heLAvnu..v.N ~9C0Hnu UHCfinfiquIHdvanxfl: munLHIv LVHIXGUHN> wk \hvw HkAW-Hfui— wawxh~fi
I .09 1 UhnIUn nkfi—n - ”a a. 3 In FJIflrhcrL-L-Ih C.:.IU-!IU P‘vflt-hhvfifimerh £.: .~ NusmVINfith in}. push :95 c‘

Turn: '5‘ #--:h u. of. My.“ IOCIH-flwvw Abe I NI ENQSV-Ns

ooscwucoo

 

 

.OH I a .Amaoaum>nmmno caused you ammqu m.uamosumc mo.ov m.
N N
mes Hms ems HNH oo mON I o WON
N.H h o H.N h a v.m h a N N
mes «NH mNH FNH luv oo em I o WON
N N
mes MNH mmH NNH 00 em I 0 so
o.m n mI e.N h s m.s a m N N
n was mas NmH mNH “on 06 am I o wON
N N
was «NH HmH HNH oo wON I 0 so
0 N + HI mes m N + m mas m m +.mH mma NNH\ roe Noo am I No »ON
.mm a .mm M 4m .mm a m mo nozbq omsaqomHV
.mmaQ cam: mm .mmao new: a .mmao new: m m . mmsetz smoaaqHszm>

 

 

.saEKHE

mm M 30am oooan humans definomun one: .Houusoo u ADV .oumn undo: H mm .musm
Imoum muouum Hmanomun u ems .ousmmoum macaw ofiuoumo u mom. .ousmmoum Hmwuouum
oaswummm H mm .wsouomm> whommn cooHn oasmmonwmwn can Ufixomua .oasmmonoman
Ioflxommn spa: coaumassflum Houmooouosmno cauonmo ou noncommwu nEmeuom omnum>¢

.H wanes

 

 

 

. :“HE\NE

O: In 3Oflu VOCHQ \AIHMWJHQ -HnmfiZUQHQ :10 I HOIHUCOU H «U» .mUOOHQ MUCH—mu “No new IIII -NIN
anunvnv—au Ruin-fl: nJaIIaAvunvahU hwfld cafinflP-mvd NAJ "n .fiva~ o3AUHIu nufifl) MUHHIINMU-ANHVU .Ilu >.U..N 033W“ nhflIhv>
n 111—74.. Nan .. >u—..- I >2~NJ o. :u9~> .-.,H...L Ivan nuavav ~ Q Ud-nha.-~U.va.~\fln~ mv-.... .IUHIUfiOAw\AI- \UN.~N~N-..u-fihflnw\fi-

Ilpa u. x. u. as»... n~ d a 3 n.... «I oils - -.:- u. a I... .nfl:v o.~ptuvni Hau..-IU-MU iv ii...» thth AM u n..\nb!.u-AIvnflhwq-lb H. dun-Ni H FII~AI~.N fivhiufllflpb>< I 09‘. at NQIN-a.~r

.oa H a .Amcoflum>uomno UoHHom How #moulu m.uco©sumv mo.°va«

 

33

 

 

 

mm.m ONH Hm om Noo HON I No wON
o.H H o s.o H H N N
mN.s mOH Hm as ice oo Hm I o WON
. N N
Hm e «H om Hm oo Hm I o
5.0 H o N.H H H N N
mN.e NHH om om Hos oo mm I o wON
N N
mH ms Hm oo HoN I 0 so
m.o H o m.o H o N N
mN.~ oHH ms Hm Hos oo mm I o wON
No .mm H .. >o .mm H >m Aoon omsaqomHv
mm m .mmHo cams m .HHHQ cams m mmpetz mmoeaHHazm>
.GHE\HE

mm H 30am oooan humane Hmwnomua comm .Houusoo n HOV .oooHn macaw no mm H mm

.oooHn macaw cauouco Mo sowmeou no u om .30Hm swo> oaacnmoo u >Um .3oam cwm>

Hmanomua u >mm .msouomm> muommn oooan owcmmouomms use oaxomwn .owemmouuma:
IUonmms zuflz soaumassflum uoumoomuoamno ofluouco ou noncommou QEHHoHOM ommum>< .MH manna

 

 

. EflE\NE

mm. H. 30am 00043 >IHQUHH... HQflCUQHQ Show: .HOHUCOU H «U» IwaMIH UHQQQ I.“ m- .vaHlm
IEGHQ >I~50I~Q ~Fud£nvnwhnu fl INCL IQHSNQHWIHQ NSCfim muflUOHFuU “ “rum IQNDQWQHQ HQWIHvaIHfiu
UqECI~E>W I. "In; I>E0UC~VQ> HGOIL a... UOOHQ UflCawflUhQQk-k Hut-H Uflxcawxfln \U,.HCo~m.UIHmvnw\An~

lUan»..>—.— 5“}: Cnv.&fl.~3E..&l LCJAmCCaanU—tmvchv mVfiUthquhv 09 IQQCFvnfimmeH QEiINmVIHOIIfi emvaHrsvbd‘ IN 0.50.3.5

34

ooscflusoo

 

 

 

 

.MH H C . AmGOHUM>H0mQO ©0HHMQ MOM ummvlu. m.UGw©Dumv mo .0 V me.
N N
eOH HsH mHH NHH oo WON I o wON
v.N Heb m.m Neva H.m HemH N N
emH nNH OOH sHH Hos oo Hm I o HON
N N
smH mmH eNH qHH oo Hm I 0 HO
H.N H NI s.v HeHH O.v HwOH N N
OmH VNH HHH mHH on 00 em I o NON
N N
mmH . OHH omH nHH oo wON I 0 HO
O.N H O e.O HHHN H.O Hwem N N
omH OHH OHH OHH on oo Hm I o HON
.mm H .mm H am .mm H m mo Aoan omeaqomHO
.mmHo cows mm .mmHo new: a .mmHo new: m m mmoetz smosaHHezm>
.cHs\Hs
mm H 30H“ cooHn humane Hmwnocun new: .Houucoo HOV .oumu undo: H mm .ousm

Locum muouum Amanomun H «mm
.hEouomm> nouns woods owemmouomhn one oaxommn .owsmmouoahn

owEoumMm

Iowxomhs rues cowumassflum Houmoomuoeono cwuoumo on noncommmu AEHHmHom ommuo>4

.ouommoum macaw ofluoumo

mom

.ouommoum Hafiuouuc

.N magma

.cwE\NE mm I kon

«HOOHD XHUJHQ Hafizoflhfi can»: I HOHUZOU H «U» IUOOHQ GDCflm M0 Moe an IQ IUOOHQ
$35.3 UdU.C..-.~U LC 50w 1:me NO .I.II. NC: I30HN Cflmw.) Uflfiflinwnwhv nu URN IRON.“ Cflmv)
.- E. a :U a... I. r.- 1. )2: I >..:. . C~uro> Laud L 5. wuauavHQ Ufi H.~o~mv.JIHIUN.~\fl.I~ mu: flu U MynOlLINN \Ufl:fi~.unuIHmvfi~\a Na

in.- u VAAIvE—xr-n n-J « 3 unqu— due — a:.. H I. I Idnb «aalIUIIHIIwIHAUCNnbfi-YV MUW #0-»:ch 3U sums-nunnauaimohfi Pant! finWIHCIH «HUNQEIL aluv>< o HIMI‘ .vaNIIIINHVrNI

35

.mH u : .Amsoflum>ummno UoHHom HOm Hoopla m.ucoo5umv mo.ouImH

 

N

N

 

HO.H ONH pm me oo HON o HON
0.0 H HI H.O H O N N
5N.e OHH OH NH on oo Hm I o HON
. N N
5N s «H mm as oo Hm I 0 HO
m.O H H 0.0 H O N N
mN.e OHH em . «a Hos oo Hm I o HON
. N N
NO O OH OH we 00 HON I 0 HO
H.H H m O.H H O N N
ON.n mHH mm as Hos oo Hm I o HON
No .mm H >o .mm H >m HozaH omsaqomHv
mm m .mmHo new: a .HHHQ new: m mmosxez-wmoe«HHezm>

 

‘4‘111 J‘ 11“i iii 4‘

.cHE\HE mm I son

oooHn mnounm Hmwnomnn coo: .Honucoo u AUV .cooHn msch mo .m H mm .GOOHA
macaw cwuouwo mo coamcou mo u mom .3on sfio> omenmoo n um .30Hm :Hm>
awesomun n >mm .NEouomm> nouns oooHn oacmmouomhn use caxomm: .oflsmmouommn
Iowxom>£snufi3 coaumHsEHum MonmoomHOEono vapoumo ou noncommmu nEHHoHom ommuo><

IMN mHQMB

sun and ruse;

A represe
are and forel
§55 fixture is
5:3: an expert
:c:'::ol period
533 control ga
TEltilatory ga.
ilcod perfusinI
315.151}! from 1
its sinuses deI
byanarked im

53".. v
.uOuSlon pres:

I‘m

‘1‘.“
.‘.lug no diff‘
i915.

Caretid

 

 

36

skin and muscle. The only change in heart rate was an in-
crease during chemoreceptor stimulation with hypercapnic
blood.

A representative response of the systemic arterial pres-
sure and forelimb perfusion pressure to the hypoxic—hypercapnic
gas mixture is presented in Figure 2. This figure was taken
from an experimental recording following vagotomy. During the
control period the extracorporeal lung was ventilated with

the control gas mixture (20% O — 5% C02). Upon switching the

2
ventilatory gas to 0% O - 20% CO the O tension of the

2 2 2

blood perfusing the carotid sinus perfusion circuit fell
rapidly from 105 to 20 mm Hg. The pH of the blood perfusing
the sinuses decreased from 7.28 to 6.91. This was accompanied
by a marked increase in systemic arterial and brachial artery
perfusion pressure. Outflows from the brachial and cephalic
veins were not altered during chemoreceptor stimulation indi-
cating no differential effect on the skin or muscle vascular
beds. Carotid sinus perfusion pressure remained relatively
constant with any changes being immediately compensated by
adjusting the variable resistance clamp on the sinus outflow
cannula. Upon returning to ventilation with the control gas,
systemic arterial and brachial artery perfusion pressure
rapidly returned to control levels.

A typical response to the hypoxic gas mixture following

vagotomy is shown in Figure 3. Upon switching from the con-

trol gas mixture to 0% O - 5% CO a rapid fall in the O

2 2 2

37

 

......

.......................

. I . . . . _ _ , . . . . . _ . l i , . _ H . N . . . . . N . . . ,. . .

. . . . _. . . .. . _._ .. . . . . . . . . . . . . . _ . _. _, . , .. ._ . .. ,1 m. H , ._., .. . i . .. ... . . . I. . . \ ,.. \
l“ll",ll”illll_.1_‘111llxllilllillliillalixai.\\\\\\\HHHHHHHHH\

Govern ‘ NUUOTON‘ N00 *0.

"03’0“ . N030 “6.939.“

.ousmmonm humans Huanomun 4mm

>0
.BOHM aflo> Amanomun n >m

.30Hm cHo> OHHmsmoo

.mHSmonm Hofluopum OHEmumwm H mm
.oooHn macaw mo mm H mm
.musmmoum wscwm ofluonmo u mom
.UooHn macaw ofluoumo mo cofimcou No u mom

.moo coNHEouomw> m CH oooan oasmmonommnlowxommn nufl3 coflucasfiflum
Howmmoouosono ofiuoumo ou uncommou HcHsomm> QEHHoHom o>Humusomonmm

.N musmflm

38

  

m ouomflm

E25 05:.

”WU,W WWUmWWI.HM M.....Wh.m.tcfij\1:0¢fi>i

 

 

 

 

 

 

 

I“ I“ L.

.rHHLF

  

I :3.

 

 

t I.III.H|. IFII. II.

 

 

 

 

39

 

 

. i‘.‘\I‘\ ...... /)I N

lll‘ltllll'lldl‘lluolt .. . ... .... ............. .. . i
. ..._ ..... ..H..l_ 1..” ........ .i.... .. ,,....._._ ....I. \ ...... ... 0€§
.I.......... ...._H,.. ......... t....,.. .._ ..\....~..__.. ...... «H‘
.. ................ ..H _._....,l....... ....... 1.._.,,,,_._.._. , .._._.. \ .‘cw 8N
_nl_::ll...:_“N1:lltflilllflliaiilllaaa.:l.l.l_\fl_\\\\\\\ \.:..,.\\\\\\I

09*“ 09*“ NOV:

N°$°N "030‘ “0:0“.

Houmooonoamno

.mHSmmon huounc Hmaaomun n m

.3on cwo> oHHmnmoo u >0

.30Hm cflw> Hcflsomun u >m

.ouommoum Hoanouum caaoummm u m

.UooHn mocwm mo mm H mm

.ousmmoum mscflm cauoumo n m

.oooan macaw Uwuoumo mo cOHmcou NO n mom

.moo Umuflfioeomm> m sfl oooHn oaxomma nuHS :owumHsEHum
pfluoumo ou uncommon HmHsomm> QEHHoHOM o>flumucmmoumom

.m ousmHm

40

m ousmfim

issue:

 

0525 M .. i
n¢u>nfi W H H

II. E. I..I

   

 

 

 

 

 

 

 

 

. . . , ..I. . .1. III . Ill
, . 1. h b b» I F I
I! at: :1: 1 I

 

 

tension of tin
5:225 blood w
:aratid sinus
gerfusion pre
vein outflows
shift in flow

tlcn with the

may

-

5..-;
I"-u=‘cn pre

A tYPica

"I'h the hype

figure 4. Ac
L

13‘02‘ 20% I

Q

5

liahe
3 ..ly' prOL‘

In.
a
. ‘
u‘fi‘

OciatiOn

'ne .
25...!
‘

ined un Ch

'1
HIE
SSUre inCr.

Reaged from

Isre
not Sign

41

tension of the carotid sinus blood occurred. The pH of the
sinus blood was uneffected by this gas mixture. At a constant
carotid sinus pressure, systemic arterial and brachial artery
perfusion pressure increased markedly. Brachial and cephalic
vein outflows were not significantly altered, indicating no
shift in flow between skin and skeletal muscle. Upon ventila-
tion with the control gas,fsystemic pressure, brachial artery
perfusion pressure, and P02 of the sinus blood rapidly re-
turned to control levels.

A typical reSponse to carotid chemoreceptor stimulation
with the hypercapnic gas mixture after vagotomy is shown in
Figure 4. After an initial control period, ventilation with
20% O2 - 20% CO2 was begun. The P02 of the sinus blood rose
slightly, probably due to the effect of hydrogen ion on oxygen
dissociation (Bohr effect). While carotid sinus pressure
remained unchanged, systemic and brachial artery perfusion
pressureincreased markedly. The pH of the sinus blood de-
creased from 7.28 to 6.94. Brachial and cephalic outflows
were not significantly altered. After returning to the con-

trol gas mixture, systemic pressure and brachial artery per-

fusion pressure rapidly returned to control levels.

Intestine

 

Table 3 shows the average responses of systemic blood

pressure, heart rate and the vascular responses of the ileal

42

..................

 

IIIII..-, [If I L flair H L eiitlr tutti.
“H._HMMMMM_..MHMMHHmHHHR_.__H\n\HHHH\_M. .............. \.\H\.H\\\
l___ i_llllt‘\i.rillwilllllrl.ilrrlili.\_iii.\\\\l\\n \\\\\\ \

«00.10»! 00 wTON\ U
ROI-n ON I” N030“
.ouommoum wuowum Hmwnomun u fimm

.30Hm aflo> oaamsmmo n >0

.30Hm cflw> Hcflnocua u >m

.oHSmmon Hcfluouum OHEmUmmm H mm

.oooHn mscflm mo mm H mm
.ousmmmnm macaw Ufluoumo u mom

.Uopo mscflm cfluosmo mo coamcou No n mom

.moo UoNHEouomm> m CH cooan oecmmouommn nufl3 coaumasfifium
Hoummomuofimno cwuoumo on uncommon Hmaoomm> QEHHmHom o>aumucmmoummm

.v onsmflm

43

v musmfim

15.52::
a 0 I .v N o

 

 

 

 

 

 

 

Stevie? . A .
lwIanmnerl.....

   

 

> .t vv n HroHL3 ucoEomm HooHH Zeno 42
.. u I. I . II
I 33~H UCH—H H&w.Ho CHHQIHCvaE CGL HOHHCOU I «OH .UOOHQ mchm M0 .2Q H IQ
.CCOHL mchm UHHOOPU MO COHmcLH O H CH .UHMH Hume: h :2 .thmmUHQ COHmDHHUQ
HcoEtlz :wzeHH ; .OHZHmQHQ .HUHHUHHH UHEOmem H VQ .QHDHWUHQ WSCHW UHUOHQU

I >50 HCHHHL> .HIHHIHHH UCOHQ O.HCQUUIHUHITCH Tin. UfiXOanC IUNHHQUIUIHUQACI UHXOQNC
>CHC H... 1) 9H. HfiHHIHZIIH UHJ: H OH UH :Q-UCI HleNICIU refinvl>2 C H H3 504%. III. HIIHHHHHHH U m INAHUANUIUFH IN
HLH o...p..s..u Ion-.IIHnflanHHH dew ochEsefiwnw IHnItvfi— .LAU NHHH-JUHHOII> IU~IumeIHti>< IMI e~fl~puflfi

thy—HEAMAQHHIB I-

a-Ha .3 «an-.4
Av a

1.3.7:..-

44

.m H G H AmGOHHMNVImeQO UGHHMQ HON Hmwfllu WHIIwflwvanvmv meoo Vnmkla

 

 

 

 

 

 

.m u : .HmaOHum>ummno Umnwmm How nmmuup m.u:m©:umv mo.ouvm*
. N N
am m mma NHH mma mNH Hoa oo wON o wON
o.m H m m.oH HHHON N.v H««mN N N N
mm.n mma me mHH HOH moa HOV 00 wHN I o mON
Nm.b ma NmH ova mmH NHH Noo wm No mo
m.N H ml.. H.v HHHmH m.m “*HNN N N
ov.H HmH moH mNH HHH NHH HoH ou wwm I 0 wow
mm.w mH NoH Nma mmH NHH Noo NON No we
o.N H «I n.mH “*HHH m.m «*HNH N N
mm.n omH 00H HHH oHH HHH HoH ou Hmm I o HON.
, NZOBOOHHSI mmemfl
mm.o HH mmH Hm mmH mHH moo mom No we
m.m H ma m.m H m m.m.H«me N N
mm.n HHH moH an omH NNH HuH ou wwm I 0 wow
wzoeowm> mmommm II
No .mm H .mm H Hz .mm H m mu Huzoq amemqomHH
mm m .HHHQ cams mm .HHHQ 2mm: m .mmHo cam: m m mmpetz wmoeaquzm>
III I IJHHIII I
.0 v« u unmflmz ucmfimmm Hmmafi cam: .GHE\HE 5H
n 30Hw ocean mumuum OHHmucmmmw ocmww .Houucoo u HOV .UOOHQ macaw mo mm H mm
.UooHn msch @Huoumo mo concmu om .mumu unmwn H mm .mHSmmmHm :onanmm
unmamom mmHH u «Sm .wusmmmum Hwflumuum oafimummm H mm .wHSmmmum macaw cwuoumo
n m m .m&ouomm> Hmumm oOOHn oflcmmonmahn can oaxommn .oficmmonmmmnluwxommn
suflz Ucm meouomm> muowmn UOOHQ oasmmoummmnloflxommn nufl3 coauwanswum Hoummomu
.m manna.

IoEmno GHHOHMO on waflummygfl mo uswfimmm HmmHH uo mmmaommmu Huasomm> mmmum>¢

segent to per
t};cxic-h;.'perc
'1y;ercapnic, h
lite only sign:

irarease in 5;.-

rate before v-

C.

- I
acreases 1n 5;

gressm-e Occur

Sental 9a5es .

 

 

w.§0real lu
”aging the
fix: .
«I13
reased marl
‘uyf‘. F
”anged h
‘55).“ 'L
yskased
f

t“. . “5
u 1n

 

 

45

segment to perfusion of the carotid chemoreceptors with
hypoxic-hypercapnic blood before vagotomy and with hypoxic-
hypercapnic, hypoxic and hypercapnic blood following vagotomy.
The only significant response produced before vagotomy was an
increase in systemic arterial pressure. The changes in heart
rate before vagotomy were insignificant. Following vagotomy
increases in systemic pressure and ileal segment perfusion
pressure occurred during ventilation with each of the experi-
mental gases. Systemic arterial pressure increased to a
greater extent (36%) during hypoxic-hypercapnic stimulation
than during hypoxic alone (20%) or hypercapnic stimulation
alone (25%). Similarly, a greater increase in ileal segment
perfusion pressure occurred during hypoxic-hypercapnic (37%)
than during hypoxia only (12%) or hypercapnia alone (17%).

No significant changes in heart rate were observed.

A typical response of the isolated ileal segment and
systemic blood pressure to carotid body chemoreceptor stimu-
lation with the hypoxic-hypercapnic gas mixture after vagotomy
is shown in Figure 5. During the control period the extra-

corporeal lung was ventilated with 20% O - 2 % CO After

2 2'
changing the ventilatory gas to 0% O2 - 20% CO2 systemic
arterial pressure and perfusion pressure of the ileal segment
increased markedly while carotid sinus pressure remained
unchanged. The pH of the blood perfusing the carotid sinuses

decreased from 7.45 to 7.00. In this animal fluctuations in

the intraluminal pressure of the ileal segment appeared to

46

..,_.i_.,::___:::l.i._.e. \ii.i.i.;.,__._l._..i.;.;,..i.\...__i.._\...\.\.g. .:;. _.... ..._..
“00*“-Nuu . "00.30“ ‘ \\ \ \ . \ x \ x x. kw 0‘
“OI-19°“ “0 Av

.munmmoum coflmSMHmm ucmfimmm Hmoafi n m
.mhsmmmum Hafinmuum owEmUmmm H m

.Uooan mscflm mo mm H mm
.ousmmoum macaw vapoumo n m

.ucmEmom HmmHH mo oHsmmmHm Hmcflfidamuucfl u 2
.Hoo

pmNHEouomm> 0 ca pooHQ oacmmoummmSIUflxome nufl3 COfluMHDEHum Hoummowu
loamno pfluoumo on ucoEmmm Hmoafl mo oncommwn Hmasomm> m>fiumucwmoumom .m musmflm

47

m Gunman

E25 «E:

 

 

iecrease during
return to the ‘
:ent perfusion
nifluctuatiOI
agnitude.
Represent
vagotomy are 5
control gas mi
sxeand ileal
while carotid
iecarotid si
mehypoxic 95
than the cont:
“2M1 fluctutl
zheileal Sec:
Stilulation.
Pressure and
toControl 1e

 

A tYpice

astemic 1310}

h hypercagl

 

48

decrease during chemoreceptor stimulation. Following the
return to the control gas, systemic pressure and ileal seg-
ment perfusion pressure rapidly returned toward control levels
and fluctuations in the intraluminal pressure increased in
magnitude.

Representative responses produced by hypoxia after
vagotomy are shown in Figure 6. Upon switching from the
control gas mixture to 0% O2 - 5% CO2 systemic arterial pres-
sure and ileal segment perfusion pressure increased markedly
while carotid sinus pressure remained unchanged. The pH of
the carotid sinus blood decreased from 7.46 to 7.36 because

the hypoxic gas mixture (0% O - 5% C02) contained more CO

2
than the control gas mixture (20% O

2
- 2%% C02). In this

2
animal fluctuations in the intraluminal pressure and tone of
the ileal segment appeared to increase during chemoreceptor
stimulation. Upon returning to the control gas, systemic
pressure and ileal segment perfusion pressure rapidly returned
to control levels and fluctuations in the intraluminal pres-
sure and tone diminished.

A typical response of the ileal segment vasculature and
systemic blood pressure to carotid chemoreceptor stimulation
with hypercapnic blood is presented in Figure 7. After a con-
trol period, the extracorporeal lung was ventilated with
20% O2 - 20% C02. The pH of the sinus blood decreased from

7.42 to 6.91. Systemic pressure and ileal segment perfusion

pressure increased markedly while carotid sinus pressure showed

49

4......_.yj.g....._;; .\.,_.\.
.....:::.:_.._.z..._,::::..\,:\\:. .......\.......\.r 0‘
U

.ousmmmum GOHmSMHom acofiwom Hmoafl u m
.mnsmwmum Hafiuouum UHEoumMm H mm
.UOOHQ mscflm «0 mm H mm
.mnsmmoum madam pfluoumo u mom
.ucosmow Hmoafl mo whammmum HmcHESHmnpcw u z

.006 pmNHEouomm> m sH pooHn oaxommn nuw3 :oaumasfiflum Hoummomu
loamno pfluonmo ou ucoemwm Hmoafl mo oncommmu amazomm> m>aumucmmmnmom

.m mupmflm

50

 

Time (min)

4

 

Figure 6

51

r : h. _ w_:._l...;_:\:i:\iq.iste:i:>:gToV

.. ,.H.H _._._ ._. ..Ki.~.;._\,_.l_ ._. “ O
_ M ___._._._ _ .__ _ l a L 53%;... _ i L l l N O“ 0.93“ N“
r L _ _ U “”06“ “03°“ U
.oHSmmmum coamsmumm ucmemmm Hmoafi u mzm
.mMSmmmum Hafiumuum anmumwm H mm
.pooan mscflm mo mm H mm
.muammmum madam payoumo u mum

.ucmamom Honda mo whammmum amnespamuucfl u z

.mov pouflfiouomm> m CH pooan Oficmmoummmn spfl3 :OflpmHsEflum Houmooou
Iosmno cwuonmo ou ucwEmwm Hmmaw mo oncomwmn HmHsomm> m>wumuammwummm .h munmflm

52

  
 

Time (:nin)

nacho,

 

 

<:- 30““?!
.2496“);

 

Figure 7

Little change.
aggear to diffs
geriod. Upon r
3‘.i ileal segme
:ontrol values
The avera
5E'stenic blood
carotid chemo:
Vagotomy and V
blood followil
"7" Systemic
PreSSure did
Following Vag
hE‘PerCapnic c

Stimulation «

‘pcx‘l‘c‘hYpe
Superior mes
EiCh expeerr
:creaSed m

53

little change. Intraluminal pressure fluctuations did not
appear to differ significantly from those of the control
period. Upon returning to the control gas, systemic pressure
and ileal segment perfusion pressure rapidly returned to
control values.

The average responses of the superior mesenteric artery,
systemic blood pressure and heart rate to perfusion of the
carotid chemoreceptors with hypoxic-hypercapnic blood before
vagotomy and with hypoxic-hypercapnic, hypoxic and hypercapnic
blood following vagotomy are shown in Table 4. Before vagot-
omy, systemic pressure and superior mesenteric artery perfusion
pressure did not change. The heart rate was also unchanged. 4
Following vagotomy, systemic pressure increased during hypoxic-
hypercapnic chemoreceptor stimulation and with hypercapnic
stimulation alone. Systemic pressure increased by 37% during
hypoxic-hypercapnic and by 23% during hypercapnia alone.
Superior mesenteric artery perfusion pressure increased with
each experimental gas mixture. Mesenteric artery pressure
increased more during hypoxic-hypercapnia (50%) than during
hypoxia (17%) or hypercapnia alone (15%). The heart rate was

not altered significantly by any maneuver.

Kidney

Table 5 shows the average reSponses of the kidney, sys-

temic blood pressure and heart rate to perfusion of the

 

 

 

 

.2HE\~E was n ko~m noose

>h3uhfl UflkQUCCEGE HOflRQQSW C602 MHOHUCOU N «U» .UOOHQ NBCflm N0 mm H :Q
uquAUHn m~.C.Hmu Ufiuadhflu .. AU CO.«..mu.Cva NO H Oaw omflmu Ukflumv: uh ~w- cmvhzmwmwmwhnw \fiMmVUch.
Uwhiapzvfifip: LC~u~012I P 2.0; .0L:EEGL€~ HGHkUUHfi» Um_=aw.~_w.\nmw nu UMW .mwhsmmmvhm meQNW
«v_ .....~._...u H 3...»; .>..—A»~n0—.fl.> «hr-fa: Tau0~n~ Cufica~€thUa~>C meta UWXEXQNQ \Uflcahfiohu-u,.fl.l~\a~fi
.;»v_ X..._>.- .. o '3 -.....~ 5...». ..u~..\\/ e.,--~...~.:~ ~zvn-A~ rvu ...»-...r.au~o.\.~\A—~Ilv- Y«AV..-A..~ as s ‘3 a..~‘ ufi.-::.‘ s5...
-.- ..-nI.-tl nn-ubnvnan.- .uu 0.1 urvvi A. t oz. .0. U .I'V .b‘ It. ~Pbl!F.§a\-.I In»! III. \-nl lint III.iI.i-ou. ~r‘OIiyh ONNIQtSIV\.l4.\

 

54

 

 

 

 

.v H c .AchHpm>Hoon Umuflmm How umoulu m.uco©sumv mo.ouvaN
.m u : .Amcofium>uomno pouflmm Mow umopnu m.ucmp5umv mo.o”.mN
OO.O HHH NNH ONH NNH NOH Noo NON . No NON
N.N H N N.v HNNmH N.m H«¥MN N . N N
ON.N mOH HNH NOH HOH NOH Nov 00 NNN . o NON
NN.N NH NNH NHH ONH NHH Noo Nm No NO
m.H H NI m.m Hrsha v.5 H mH N N N
NN.N NO «NH HOH mHH NHH Nov oo N+N . o NON
NO.O NH NNH mmH ONH mOH Noo NON No NO
O.H N N O.OH NNNHm H.N NNNNN N N
mN.N Na ONH NOH NOH NOH Nov 00 NNN . o NON
Nzoeow¢> mmema
N0.0 NH OmH OHH NNH OHH Noo NON No NO
O.N N N N.N N NH O.m N NH N N
mN.N NOH NmH OOH .1 NNH HNH Nov 00 N+N u o NON
.Nzoeoo<> mmommm .1
No .mm N .mm N azm .mm N m mo szaq omaaqomHO
mm a .NNNO new: mm .NNNO new: a .NNNQ new: a m mmoetz mmoeaquzm>

 

 

‘ 4 J 114‘44411‘ ‘4]

.QHE\HE vba n 30Hm UOOAA

Nymphs oanoucomoe nowHoQSm coo: .Houucoo n .pooHn macaw mo mm H mm

AUV

.pooHn macaw pflwoumo Wm :owmcoy «o u mom .oumu ammo: H mm .ousmmoum humans
ofluoucomoe HowquSm H mm .mHSmmoum Hafinounm owfioumwm H mm .onsmmoum macaw
Uwuoumo u mum .maouomm> Hovmm pooan owcmmouomhn can oaxommn NUNQQMUHomhn

loaxommc nua3 can maouomm> oHOMon pooHn vasomonommnlowxommn suds :oaumHSEHum
uoumoooHOEmno UNNOHmo on muonum oauoucwmofi uoflnwmsm mo momsommou omnum><

.v manna

 

 

 

 

:1 Co .uuflo coo: z: .522 552 so .ttwc cat: o “lan

 

 

41"“

.CflE\HE OHH H 30H“ UOOHQ Khmuhfl HQCWH

Page“ O.HO.HJP~OU a" ADV QUOOHQ mudgufim .mflo :flm n” IAN omUOOHuhN mudgufim MUHUOMMMU “W0 EOflmcmu
no I... NAVL -0.th JHUmvz 1..., z: -Ohsamoxunw \AuHmWUszw .HflvawzH “ Zak .Utflzmumumxul HQflHmdUL-W
adv-nab {NA-u- .1 $4.4 o ruvtu—u-a.u.vl-N~ 3:: v 3 H4 m. ya nulsfvvv fin mU.N u \wiholu Okvfiv> .Hflv‘u LH Ev NUOOM Had (a NHNQHUMVLNAUTNXNN
mean!» we. vh.,..—\fl,- \ruw.N.—ex-e...!l.v.~\f.—l--4~.vh.vn..~\fl.~ -d ~59 Pv-PV \A...flv~A.v~,w-nv\f fiv.-..v...~y..v- Pvfian~A~ nus -A..-%.f.vt~1s.NNA~\
I .u‘ VA. ->.- n. U ‘3 nu-wd .12.;- qI-.- o.‘ In: ssh-Unurb.uav.-flbnfixb ~U~1 havhlhrv “Hui. lV~&~.hn.u-illfinmv.~ Lfln.in-ui z oNV\H-c..c,hn..ri\l< 01,15.

m‘ ~ h.\lk‘.Nu

55

.OH H C N AmCOH#M>H®mQO Umhflmm HOW #mw#l# m.#C®UD#mV m0.0 V m¥

 

 

 

 

NO.O NNH OOH ONH NNH NOH Noo NON No NON
N.H N N- O.N N NON O.O N NON N N N
ON.N ONH OOH ON ON HOH Nov oo NNN . o NON
ON.N OH HOH ONH ONH OOH Noo NO No NO
H.N N O N.OH N NON O.O N.NOH N . N
NN.N NHH OOH NO HOH NOH Nov 00 NNN . o NON
NO.O OH OOH OOH ONH OOH Noo NON No NO
O.O NNN O.OH N NOO O.O N «NO N N
ON.N NHH NOH HO NOH OOH Nov oo NNN u o NON
Nzoeou<> mmemfi
O0.0 OH NOH ONH ONH NHH Noo NON No NO
O.H N H N.OH NNOO m.N NNOH N N N
OO.N HNH HOH OO ONH OHH Nov oo NAN I o NON
Nzoeoua> mmommm
No .mm N .mm N m .mm N O we Nozoq OmeaquHO
mm m .mmfla can: mm .NNNQ new: m .NNNQ cmmz m m mmoatz amoequazm>

 

41114444 4

.GNE\HE cad u 30am poodn muouum Anson

comm .Houucoo u AUV .oooHQ mscflm no mm H mm .pooHn macaw pfluonmo mo coamcou
o n mom .ouwu ammo: H mm .ousmmoum humans Hmaou H mm .ousmmoum Hmwuouum
owamummm H mm .musmmoum macaw pwuoumo u mom .mfiouommb Hmumm cocan aflcmmoummmn
can owxomhn .oficmmouommnIOonmms nuw3 can Neouomm> whomon pooan oacmmoummmn
Iowxommn saws cowumadeflum MonmoooHOEmao wfluoumo on oncommou hospwx mmmuo>¢

.m manna

 

11':

carotid chemo:
vagotomy and v
blood after va
artery perfusi
the heart rate
greasure and i
:ificantly duz
in heart rate
:lation with C
J. Systemic pr
I313) than dur

:3“
“Lularly' ren

(If'r'

 

56

carotid chemoreceptors with hypoxic-hypercapnic blood before
vagotomy and with hypoxic-hypercapnic, hypoxic and hypercapnic
blood after vagotomy. Systemic arterial pressure and renal
artery perfusion pressure increased before vagotomy, while

the heart rate was unchanged. Following vagotomy, systemic
pressure and renal artery perfusion pressure increased sig-
nificantly during each experimental maneuver. The only change
in heart rate was a slight increase during chemoreceptor stim-
ulation with combined hypoxia and hypercapnia. The increase
in systemic pressure was greater during hypoxic-hypercapnia
(31%) than during hypoxia (19%) or hypercapnia alone (23%).
Similarly, renal artery perfusion pressure increased more
during the combined hypoxic-hypercapnia (65%) than during
hypoxia (49%) or hypercapnia alone (44%).

Figure 8 presents a representative record during chemo-
receptor stimulation with hypoxic-hypercapnic blood following
vagotomy. After a control period during which the extra-

, ventila-

corporeal lung was ventilated with 20% O — 2%% CO

2 2

tion was changed to 0% O2 - 20% C02. The pH of the carotid

sinus blood decreased from 7.42 to 6.91. As the O2 tension
of the carotid sinus blood fell, systemic arterial pressure
and renal artery perfusion pressure increased while carotid
sinus pressure remained constant. Upon returning to the con-

trol gas, systemic pressure and renal artery perfusion pressure

returned to near control values.

57

.OooHn

.moo woNHEouomm> m
coaumasefluw HoumoooHOEmno vapoumo

«0030“ ‘ Nonvghofl“

“0:0

.pooan macaw mo mm H mm

.muzmmmum wumunm Hmcou H mm
.ounmmoum HMHHouHm OHEwumwm H mm
.mHSmmoum macaw Ufluoumo n mum

macaw vapoumo mo coflmcou NO n mom

ca oooan ownmmouommnIOonmmn sufl3
ou mmaommou Nocpflx o>wumucomoumwm

.m ousmflm

58

m whamwm

.5535:
o

I I l .d l l):

32.55

 

 

 

 

      

. . ”N.
x. , , . l , , . .l , HE. lirlrt. NLLrir

. ..... . Cwmqpfimfifi can
. ..L.;O.Mr..;fl.trlu .... ii. 1....r N

  

 

«Ouoxoou ‘ «agend-
«0030 «0.53 ..

A typicai
'2: stinulati
Figure 9. Af
'reztilated wi

'55P Of th‘
we 02

iecreased frc
:ixture conte
PIESSure and
even with a 1
”turning to
artery perfu

A repre
IECeptOr sti
is Show) in
ExtrdCOrpOrE
:16 pH Of t}
15:1: Pressx
While carot;
to the Cont;

‘1
‘.

e rapidl

he av
SE'Stem.

lc Pr
thingy.

59

A typical renal vascular response to carotid chemorecep-
tor stimulation with hypoxic blood after vagotomy is shown in
Figure 9. After a control period the extracorporeal lung was
ventilated with 0% O - 5% CO2 which produced a decrease in

2
the P of the carotid sinus blood. The pH of the sinus blood

0
decreased from 7.37 to 7.30, again, because the hypoxic gas
mixture contained more CO2 than the control mixture. Systemic
pressure and renal artery perfusion pressure increased markedly
even with a slight rise in carotid sinus pressure. After
returning to the control gas, systemic pressure and renal
artery perfusion pressure rapidly decreased to control values.
A representative response of the kidney to carotid chemo—
receptor stimulation with hypercapnic blood after vagotomy
is shown in Figure 10. Following a control period, the
extracorporeal lung was ventilated with 20% O2 — 29% C02.
The pH of the sinus blood decreased from 7.39 to 6.87. Sys-
temic pressure and renal artery perfusion pressure increased
while carotid sinus pressure remained constant. Upon returning

to the control gas, systemic pressure and renal artery pres-

sure rapidly returned to control levels.

Heart

 

The average responses of the coronary vasculature,
systemic pressure and left ventricular contractile force to

chemoreceptor stimulation by hypoxic-hypercapnic blood in

60

. . .

coaumHDEHum

. . . .M h . . . .. .. .. .. ... ._ l . _ , .. . l. l. .. .2 x _. N . . l N . . . ‘ i .

.. H _. , O _ .i A _ u _ . . . . . . “ougn ‘ U
Nousn-«| ‘ “0:0
"0:0“ I

. _ ‘Iccc

.pooHn macaw mo mm H mm
.musmmoum humans Hmcon H mm
.mHSmmmHm Hmwuouum anmummm H mm
.ousmmmum macaw vapouwo n mom

N
.pooHn macaw pfluoumo mo cowmcou NO u om

.moo oo~a80pomm> m CH pooHQ oaxommn :uHB
Houmooouofioso payoumo on oncommou wmcpflx o>aumucomoumom

.m ousmflm

61

m wuswflm

if as:
Q N O

O— 0
IJ‘IIIIII- Illllllllll I I I

  

 

ants—E.

mu‘

315.5

62

_ . . . . . _ . . -.3-1 ‘Cniaiacc N l\
Nousn0“ll U ‘ “03°“
“0:0“ .I

.pooHn macaw mo mm H mm

.ousmmmum muouum Hmcou H mm
.oHSmmon Hafiuouum ONEoummm H mm
.oudmmmum msGHm pfluoumo u mum

.pooHQ macaw pfluonmo mo cowmcmu No n «on

.moo poNHEouomm> M GA pecan UHCQmUHoQNQ spas
cowumaseflum nonmooouosono pfluoumo on oncommou hospflx o>HHMNcomonom

.OH musmflm

63

OH wusmflm

is. 2.:

 

315....

mu‘

3.2....
«on

64

ten animals before vagotomy are shown in Figure 11. During
the control period the extracorporeal lung was ventilated with
20% 02 - 24% coz. Ventilation with 0% 02 - 20% (:02 was then
begun at time 0 seconds (Figure 11). The pH of the carotid
sinus blood decreased from 7.44 to 6.96. As the carotid

sinus blood P fell, systemic arterial pressure increased
significantly from 60 to 210 sec. while coronary artery perfu-
sion pressure rose significantly only at 60 and 90 sec. Left
ventricular contractile force decreased significantly from 90
to 210 sec., stabilizing at a point 9% below the control value
by 210 sec. The heart rate was significantly lowered from

164 to 156/min.

The average effects of the same hypoxic-hypercapnic
chemoreceptor stimulus in ten animals following vagotomy are
shown in Figure 12. Carotid sinus blood pH decreased from
7.39 to 6.95. Accompanying the fall in carotid sinus blood

P systemic pressure increased markedly from 60 to 210 sec.

0 I
2
while coronary perfusion pressure rose slightly only at 60

sec. Left ventricular contractile force decreased from 90 to
210 sec., reaching a point 19% below the control value by
210 sec. There was no significant change in heart rate (159
to 157/min).

The average responses to hypoxic chemoreceptor stimula-
tion in ten animals after vagotomy are presented in Figure 13.
Carotid sinus-blood pH decreased slightly from 7.36 to 7.32.

As the carotid sinus blood PO fell, systemic pressure
2

65

.OH H
.CHE\HE mHH n 30am UOOHQ wnmcouoo
.ooH0w oafluomuucoo HmHDONHucm> puma u

.pooHa mscwm vapoumo mo coawcou NO u

.musmmoum HMNHouHm UNEoumNm

.wusmmoum CONmSMHom mumcouoo

.wEouomm> ouomon pooHn oacmmoummmaloflxommn Qua;

C

com:

m0>q
NOm

mm

moom

soap

IMHDEHum Hoummoouoeono pfiuoumo on oncommmn Hmasomm> mumcouoo ommum>¢

.HH mNsONn

 

66

HH musmHm
«39.33030 39...»:— 53 «no. a {co—2:3 mode...

.3 N" 38:.
uOu us:

DON 00— O

4 4 q 1

 

 

3.” w ¢

ON... 1

 

‘1?
1T
it

50>.—

A
V

.‘ODOA .1

 

oBuoq: 1,

N
‘0

 

N 0°—

‘1

 

a
a
a
on
k
a

N 80*

n on—

 

»!opoogucn NOU$ON .I «0400

67

ImanEfium

>2°hoo<>bW°l 0000\00N II ICIVOC

.oa n
.CHE\HE mHH n 30am UOOHQ mumcouoo

.ooHOM oafluomnucoo Hoasofluuco> uwma

.UOOHQ mscfim vapoumo mo coflmcou NO

.onsmmonm Hmflnounm oweoummm

.oHSmmonm coflmsmuom whosouoo

.NEouomm> Houwm pooHn oacmmouwmwnlofixommn nufl3

C

coo:

mU>A
NONH

mm

moum

CON»

HONQoooHOEono pflponmo ou oncommmn HmHsomm> Nnmconoo ommno><

.NH onsmwm

 

68

NH musmflm

«30203030 $9.23. 3m to. O «Leo—2:3 mOJAN

 

 

 

 

 

.3 “N 2:82
van us..—
oo« 2: 0

Nb 1
mm . 33 . . 1m- lwon n
6 T 3+- 3
a H N n
0.. n
w
“H
B

“VIII-In

‘ 8005 n

>£opoo<>50n «09.50" I. «0.30

69

:oHpmadEHum

.OH H
.GME\HE mHH u Beam UOOHQ mnmcouoo
.moHOM mHfluomuucoo Haasoflnucm> puma u

.UOOHQ macaw Uwuoumu mo coflmcmu NO n

.mHSmmmHm Huanmuum OHEwumMm

.wHSmmmHQ cowmsmumm wumcouoo u

.mEouomm> Hmumm wooan Oflxomhn

G

cmmz

MU>A
mom

mm

moum

sufls

HouamomuoEmzo Uwuonmo on mmcoammn Hmasomm> mumcouoo mmmum>¢

.ma musmflm

70

"

..... .w'I'Vy; .P
_ n . w

ma musmflm

7:33:0ch taxman 3m to. . {5:33. “361..

 

 

 

 

 

.mm a 28.2
3. us:
DON 009 0

Nb I

3 «I oul .. w + 01 d

.. .. . On

W n . .u>._ Lm Jr a
U o s
B “I ON+ 1 m

00—

i L

c
IOut

On—

»!opoogpmg «00.5“ I. «Oo\o0

71

increased significantly from 90 to 210 sec. Coronary sinus

perfusion pressure was significantly increased at 60 sec but
then gradually decreased during the remainder of the experi-
mental period. Left ventricular contractile force decreased

significantly from 90 sec onward, reaching a point 14% below

 

control by 210 sec. The heart rate was unchanged (158 to :Ӥ
157/min).

The average responses to hypercapnic chemoreceptor stimu-
lation in nine dogs after vagotomy are presented in Figure 14. j

The P02 of the carotid sinus blood rose, Probably due to the
Bohr effect. The sinus blood pH decreased from 7.37 to 6.92.
Systemic pressure increased significantly from 60 sec onward
while coronary perfusion pressure showed no significant change.
Left ventricular contractile force decreased significantly
from 90 sec onward, reaching a point 9% below control by 210
sec. The heart rate was unchanged (158/min).

A second series of heart studies was carried out on
vagotomized animals in which graded carotid chemoreceptor
stimulation was accomplished by perfusing the chemoreceptors
with the combined hypoxic-hypercapnic blood and with blood
having varying degrees of hypoxia and hypercapnia. Figure 15
is a representative record showing the responses of the
systemic pressure, coronary perfusion pressure and left
ventricular contractile force to ventilation of the extra-
corporeal lung with the hypoxic-hypercapnic gas (0% O - 20%

2
C02) after‘vagotomy. Following the control period, ventilation

72

.m H
.GHE\HE mad u 30Hm @OOHQ mumcouoo

.oouom oafluomuucoo HmHSOfiHucm> puma n

.oooan mscflm vapoumo mo coflmcmu No

.mnzmmmum Hafiumuum OHEmummm n

.mnsmmmnm coflmsmuom wumcouoo

.meouomm> Hmuwm pooHn Oflcmmonmmmz nuHB

C

cam:

m0>q
mom

mm

moum

:oflu

IstEHpm uoumwomHOEmso payoumo Op wmcommmu Hmasomm> wumcouoo mmmum>¢

.vH musmwm

73

 

v. magmam
«2.029.330 19:01 50* .3. . «1.3.233 HAWK...

.3 a 2.3.2

900 us..—

008 00— o

1 d 1 i1

 

 

 

ON I W $.— U>.— 1'1 W w on

ON...

oBuoq: 4%
'1'3‘A'1
38055384

 

n
& 00p

 

8001
On —

220.2333; «00$ON I «OofiON

.mnsmmoum Goamswumm humcouoo

.ooHOu mawuomuucoo HMHSOHHqu> puma
.onsmmmum ammuwuum oafimuwmm

.UOOHQ mscflm mo mm

.UOOHQ mUCHw muH¥OHMO MO GOHWGQH. NO

74

ll

moom

.mU>.H

m
m

an
mom

.moo UoNHEouomm> m 2% pooHQ UflcmmonQmQIOflxomhs no.3 coaumasfifium

HoummomHoEozo vapoumo on oncommou HmHsomm> kHMGOHoo m>flumpcmmmummm

 

.mH musmflm

75

ma whamflm

Ewes 9::

 

 

 

 

«coffin
«Ochoa I

 

 

 

 

 

 

 

76

with the experimental gas was begun and the typical marked
rise in systemic arterial pressure was observed as the pH

and P0 of the sinus blood fell. Left ventricular contrac-
2
tile force decreased remaining well below the control level.

In this animal, the coronary perfusion pressure showed a

transient decrease followed by a return to near control value.

Upon returning to the control gas, systemic pressure rapidly

decreased toward control as the carotid sinus pH and PO
2
returned to control values. Left ventricular contractile

force increased as the coronary perfusion pressure rose to

a level slightly above the control level.

Figure 16 is a representative record showing responses

to a reduced degree of hypoxic—hypercapnia (10% O2 - 10% C02) .

Following the control period the extracorporeal lung was

Ventilated with the experimental gas, which produced roughly

50% of the fall in carotid sinus blood pH and PO obtained

2

with the previous gas mixture. At a constant carotid sinus

pressure, systemic pressure increased. Left ventricular

contractile force fell slightly while coronary perfusion pres-
Sure was unchanged. Upon returning to the control gas,
Systemic pressure rapidly returned to control. Left ventric-
ular contractile force rose to a level above control while
coronary perfusion pressure remained unaltered.
Representative reSponses produced by chemoreceptor

S .
tlmulation with a less hypercapnic gas mixture (20% O2 - 10%

C
02) than that employed in the first series of coronary

.musmmmnm coflmsmumm wumcouoo

.00H0m mafluomnucoo Hmaoofluucm> puma
.musmmmum HMflHmuum OHEwumhm

.UOOHQ macaw mo mm

.UOOHQ mscflm pfiponmo mo coamcmu NO

77

mOU

mU>A

mm

mm
mom

.mow

UoNHEouomm> m CH pooHQ oacmmoummmnloflxomwn mmoH suflz coflumHSEflum

uoumoomuofimno Ufluoumo ou omcommmm HmHsomm> mumcouoo m>HumucwmmHmmm

 

.ma wusmflm

 

78

ma mudmflm

i=5 2::

 

 

 

«33nd- U
N0.5.... -

 

79

studies (20% O - 20% C02) is shown in Figure 17. At a

2
constant carotid sinus pressure, systemic pressure rose as
the sinus blood pH fell. Left ventricular contractile force
decreased while coronary perfusion pressure remained un-
changed. Returning to the control gas produced a rapid
decrease in systemic pressure toward the control level and
an increase in left ventricular contractile force that
reached a steady state above the control value. Coronary
artery perfusion pressure remained unchanged.

The average responses of the coronary vasculature,
systemic blood pressure and left ventricular contractile
force to hypoxic-hypercapnic chemoreceptor stimulation follow-
ing vagotomy are shown in Figure 18. In six animals, the
mean pH and P02 of the sinus blood decreased from 7.43 and
105 mm Hg to 6.96 and 17 mm Hg, respectively. Systemic pres-
sure increased markedly from 60 sec onward while coronary
perfusion pressure was unchanged until 90 sec when a transient
insignificant decrease occurred which gradually returned to
the control level. Left ventricular contractile force de-
creased significantly from 90 sec onward, reaching a point
27% below the control level. No change in heart rate was
Observed (14l/min).

Figure 19 shows the average responses to chemoreceptor
Stimulation with a reduced degree of hypoxic-hypercapnia
(10% O2 - 10% C02). The mean pH and P0 of the carotid sinus

2
b100d decreased from 7.45 and 108 mm Hg to 7.15 and 63 mm Hg,

 

l‘ h.
n
: Q

80

.oHSmmon cowmamumm humcouoo u moum

.mouow wafiuomuucoo Haasofluuco> puma n mU>A
.mudmmmum Hmflumuum oefimumwm u m
.pooHn modem «0 mm H mm

.pooan msawm Uwuoumo mo cowwcou No u «Gm

.006 pmNHEouomw> m ca pooan Uflcmmoummmn nuflz coaumasaflum
uoummomuoemno pfluoumo ou mmcommmu umHsomm> mumcouoo m>aumgcmmmummm

 

.ha musmflm

 

81

 

QQN

«033...? _
«0.58 I

ma musmflm

SE. 2::
Q

Q—N
fl:

Teen

 

 

floou

ovsuze

3. ”an;

«3.5.2- U
«0.5%

32.5...
«Out

82

Inseam

Om " a
.cflE\HE mHH u 30Hm pooHn humcouoo cows

.oonou oafluomuucoo HMHSOfiHucm> puma n mU>A
.mhsmmwum scamsmuom mumcouoo u moom
.mHsmmmnm Hafiuouum anmummm H mm

.meouomm> umumm cooan Uficmmoummmnnowxomms nuflz cowumH
uoumoomHOEmno pfluoumo ou mmcommwu MMHDUmM> wumcouoo mmmnm><

.mH oudmflm

83

ad musmfim

«25:033.... 19:2; 50m .3. . 3.2.35.3 Mada...

 

 

 

.mm a. 2:35.
can a:....

oo« oo. o
. d
a on n
a
a. e? . . . . 32. . . n
3 1. as I.
O ‘ a

H .A II.

M .. . 'y -
B u. 1.3. m
0 ca... .. w
H"
mm B
. . on.

22039350.. «0030“ I «030

84

IDEHum

omuc

.GHE\HE mHH u 3oaw pooHn mumcouoo cmmz

MU>A

.wunmmmnm cofimswnwm anaconoo n moum

.mouom maauomuucoo Hmasowuucm> puma

.wusmmmum amaumuum OHEmummm H mm

.weouomm> umuwm pooan venomouwmmnlofixommn nuflz cofluma
Hoummomuoemno pfluoumo o» mmcommmu Hmasomm> >Hmconoo mommm><

 

. 3 353m

85

aBump %
0‘03. .1

C
d
I
a
n.
Baum:

w
_. . . . flirt

 

a. mesmem
3.32.6302... 39:01 to. .3. . {co—2:3 MOJ...
.mm a... «.802

90a us..—

OON 00— o

 

O
N
I
1

ON... I

 

d d d 4

 

 

 

 

On—

>£o.oo<>.mo.. «0950—. I. «00b0—

86

respectively. Systemic arterial pressure increased from

90 sec on while there was no change in coronary perfusion

pressure. Left ventricular contractile force decreased

significantly from 90 sec onward, reaching a point 5% below

the control level. The change in heart rate from 140 to

l42/min was not significant.

The average responses to varying degree of hypoxic

chemoreceptor stimulation are shown in Figures 20 and 21.

Hypoxic stimulation by 5% O2 - 2%% CO2 in two animals and

113% O2 2 in three animals produced no changes in

Systemic pressure, coronary perfusion pressure or left ven-

- z-g-sz co

tricular contractile force. During carotid sinus hypoxia

of the carotid sinus

irlduced by 5% 02 the mean pH and PO
2

bJJDOd were altered from 7.44 and 111 mm Hg to 7.45 and 38
rm“. Hg, respectively. During hypoxia induced by 10% 02 the

mean pH and PO were altered from 7.44 and 111 mm Hg to 7.43

2
allCi 45 mm Hg, respectively. Changes in heart rate during
(154 to

Ventilation with 5% 02 (139 to l4l/min) and 10% 02

lSl/min) were not significant.
Figure 22 shows the average responses to a lesser degree

C>f5 hypercapnic chemoreceptor stimulation. Systemic pressure

ILruzreased from 60 sec onward. Coronary perfusion pressure

Varied with signigicant increases only at 60, 90, 180 and 210

Benz. Left ventricular contractile force declined gradually

becoming significant at 150 sec. By 240 sec it was 6% below

of the carotid sinus blood

'the control value. The PH and Po
2

 

87

oNuc

.CHE\HE «NH u 30Hm pooHQ humconoo cmmz

.moH0m mawuomuucoo “masoflhuco> puma H mo>q
.musmmmum GOflmsmnmm mumconoo u moum
.mHSmmmHm HMflHmpum OflEmumwm H mm

.mEouomm> Hmumm pooHn Oflxommn nuHB cowva
ISEHum Hoummoonoaono pflponmo ou mmcommmu HmHSOmm> mumcouoo mommm>¢

 

‘
f
‘2.

.om musmfim

88

06mm: 1,
0,03. .1

 

0“. v

ON+

em mesmem

a«:o.:c>3«no 19.3.. .31 .3. . «1.3123 mode...

.3 a 2.2.:

90« m2..—

OON oo—

 

  

33 1.

I

i III'III

ION—

 

 

»20.oe<>.3m «OUXW.N I «0RD

 

 

'

89

.m

“C

.CHE\HE Hma n 30Hw UooHn hnmcouoo cmwz

.mouom mafluomuucoo Hmasofluucm> umma
.mHSmmmnm coflmswuma wumaouoo

.mHSmmmHQ HMflHmuum UHEmpmww

.mEouomm> Hmumm COOHQ Oflxomhn mmma m npfl3

II

mU>A
moum

mm

GOflumH

ISEHum HoummomHOEono pfluonmo ou mmcommmu Haasomm> mumcouoo mmmuw>¢

 

.HN mHDmHm

 

90

08mm: %

'i’D'A'1

ONI

ON...

F“. .- ‘m
F

iii.

Hm musmwm

3.329.330 19.31 .31 .3. . «1.3123 mood.

 

 

 

 

.mm an «.333.
00« as..—
oo« oo. o
q d d 3 d
.8 u
a
s
s
. m.
m. .1
r .fi
3. w
30.. .. m
# llll l I “
10>. .. H
. on.

 

>20.00<>.«0e «OUo\om.fl I

«030—

 

91

.9":

.G.E\HE mHH u 30am UOOHQ >HMGOHOO Gmmz

.wouom mafiuomuucoo HMHDOflngnm> uwma u mU>A
.musmmmum cowmsmuwm mnmaouoo u moon
.mnsmmmum amaumuum Uflfimpmmm H mm

.weouomm> Hmumm cooan Uflcmmoummwn £ua3 cofluma
Iseflum uoummomuofimno Ufluoumo on mmcommmu Hmasomm> mnmcouoo mommm>¢

.NN musmflm

92

06mm: 33

'5'3'A'1

mm mnsmwm

3.329.330 .33.. .3. .3. . «2.3.3.3 no.1:

90« as...

can 00—

 

O
N
I
I

I

ON... 1

.

 

 

 

. .2... . . ‘

 

 

w
w

a. — a IOU‘ i a

>Eo.oo<>.«o._ «OUo\oO— I «0.x.ON

.m« a 28:
o
. o« u
a
s
s
.n
l
a
m
3. u
”H
6
on.

93

changed from 7.45 to 109 mm Hg to 7.17 and 112 mm Hg,
respectively. The heart rate remained constant (l4l/min).
An additional parameter, the Q-T interval of the EKG,
was monitored in the second heart study. Data from six
animals showed no significant alteration of the lead II Q-T

interval by any of the chemoreceptor stimuli.

Gracilis--Hindpaw

 

Table 6 presents the data from two animals showing
the responses of the isolated, perfused hindpaw and gracilis
muscle to perfusion of the carotid chemoreceptors with hypoxic-
hypercapnic blood before and after vagotomy. The data show
that systemic pressure, hindpaw and gracilis perfusion pres-
sure are increased during chemoreceptor stimulation before and
after vagotomy. Figure 23 is a representative tracing showing
the responses of the hindpaw, gracilis muscle and systemic
blood pressure to carotid chemoreceptor stimulation with
hypoxic-hypercapnic blood after vagotomy. After a control
period the isolated lung was ventilated with 0% O2 - 20% C02.
As systemic arterial pressure rose, carotid sinus perfusion
pressure was maintained as constant as possible.. Gracilis
artery and cranial tibial artery perfusion pressure increased
during stimulation. Upon returning to the control gas,

sYstemic pressure, gracilis artery and paw perfusion pressure

returned to control levels.

94

 

N N

 

 

 

 

 

I mN NmH mNH HNH mm 00 wON I O we
N N N# 000
u NH. mm. ma. OHH om on oo wwm . o mom
. om mm. mm. mm. mm. Noo wow I No .0
m N m H. moo
I wHH mva ONH mNH vma ADV OU de I O MON
szBOUm> mm9m¢
no.n vm mm moa mmH HOH moo wow I No we
m N N* 000
u so. mm 00. mo. mm on oo wmm I 0 wow
0... am mm. .m. mm. mm. Noo wow a No .0
N N H# woo
.m.. 0.. mo. mm mm. mm. loo oo .mm u 0 wow
NZOBOU¢> mmommm
mo maaflomum 3mm m «o Aozoa omeaqomHv
mm a . m m m m mmoetz wmoeaquzm>
.cHE\HE Ha n 3oam oooan muwuum mflHHomum com: .cHE\HE mm H 30am
woman swapcfln cmmz .pooHQ woman «0 mm H £m .mooan «scam ofluoumo mo coamcmu
O u mom .muommoum wumunm «HHHomnm u «H flows m .musmmmum coflmsmuom 3mmocws
u 3mmm .muommmnm Hmwumuum oaemumMm H mm .musmmmum «scflm ofluonmo u mom .MEo
Iuomm> Hmumm 0cm mucumn pooHn UHcmmonmmzlonommn nufl3 COflumHSEH#m Hoummomu
IOEmSO UfluOHmo on mHOmDE mflHHOMHm can 3mmpcfl£ UwHMHOmfl m0 mmmcomwwh mmwum>< .m GHQMB

3mm

.musmmmum cowmomumm 3mmwawn u m

waaaomum

.ouommmum cosmomuwm mumuum «.HHomum n . . m
.muommmum macflm ofluoumo u mom

.wusmmwum HMHHmpHm anmumwm H mm

.oooHn macflm mo mm H mm

.pooHQ «scam ofluoumo mo :ofimcmu NO H Nom

..moo omnweouomm> 3
me oooan venomoummhnloflxomwn £ua3 coaumHSEfium HoummomHOEmno Ufluoumo
ou mHomSE «Hafiomum com SmooCflg pmumHOmH mo mmmcommmu m>aumucmmonmmm

95

 

.MN musmfim

96

mm whomfim

$3.5 OE“...
« o v u o

 

 

 

««

 

 

 

 

 

 

 

 

 

 

 

 

 

. . . . I . . . . I . . . I . I . I . . . Ll w ..
i
. I r r I 4 L‘ n 4 I, ,1
ll , N
. . 4 . . . . . . . o . . . . o . . . . . 4 . . .. o . T s .3 .+ . J
. V ,
M. . . . . . ., . . . . . . . . . . . . . . . . . I . . . . . . a . l . u . m n
. l a m . . i a m . . _ 4 . _ r . . H . . . . . . . . . . a . . . . . l. . is I '8“
_ . . . w . u i . _ h . . _ q R . . W A E . _ _ . . w P , u m .
.L . _ 1... I... T... .. . w » I . TI» . II.— . . . » III—Ir-“ ..IL. 7.1. h ....... . .ILII .- r; v 7 IL _ ». . y . n . l I
H 3.34.. w . . I" 1.. «.1144 . q, a, .4. . ~ .01. ‘1“ v I . . I o 4 4 4 - ¢ . d c. . g III. 9 . . . . . I .M 2. T 4 a ,
w . . . . . . . . . . . . . . . 7 1,. &
M l .
A, . . . . _ . . . . . . , .x. 4 ,4
u , l
.. . . . . . . . . . Y . . . . 4 . . . . i . “SEE.
w . ‘ ., . . . . . . I o . . . . . . Ir». . a i
.. a
£55,... .33?
A .(u. . 5 u.
_~ . . . . ,. h . ; . . , . . . . ,. f .l p . . . . . _ . . . .
,V i l
V . . . . . I . . . .
r w . l . _ . w _ l _ I _ . ,

 

 

97

Table 7 presents the results from the three animals in
the second series of hindpaw studies in which the skin of the

hindpaw was circumferentially sectioned and the cranial

tibial arteries perfused. Hindpaw perfusion pressure did not

appear to change during stimulation before vagotomy and only

increased slightly following vagotomy.
The results from the two animals in the third series of

studies are presented in Table 8. In this series the hindpaw

Skin remained intact and the paw was perfused through the

cranial tibial artery. The data show that the systemic pres-

sure and paw perfusion pressure increased during chemoreceptor

8timulation before and after vagotomy. Figure 24 is a repre-

sentative record of the responses from the third series of

hindpaw studies. Before vagotomy, ventilation of the isolated

lung with 0% O2 - 20% CO2 produced increases in systemic pres-

mare and paw perfusion pressure. Ventilation with the same

gas mixture following vagotomy produced a greater increase in

SYfitemic pressure and paw perfusion pressure. Ventilation

with 10% O2 - 10% CO produced a lesser degree of hypoxic-

2
hYPeJ’mapnia. This induced a smaller increase in systemic

Pressure and paw perfusion pressure.

I.IIVJXAUAIDF- II1<1I

 

 

 

 

 

N N

 

 

 

wo.o ow wo omw .o. oo wow I o wo
w w m. com
o... www mo oww mow foo oo wmw I 0 wow
I mw wow wow omw woo wow I wo wo ww woo
w I w
I mww oww .m. .ow loo oo www I 0 wow
I ow mo ow. mww woo wow I wo wo o
I oow oo wow ow. loo oo www I 0 wow
wzoeoow> mmemw
% oo.o ow m. omw oow woo wow I wo wo ow woo
. w . w
om . wo m. oww oow foo oo www I 0 wow
I Hw om. w.w wow woo wow I wo wo ww woo
w w
I oww mow .ow mow foo oo www I 0 wow
I ow mo wow oow woo wow I wo wo a. mom
N N N
I oo. ow wm. oow foo oo www I 0 wow
wzoooo<> mmowmm
mo wo , snot. . m . mo .ozoq omomqomwo
a o m m mmoexwz wmoequazm>
.cws\ws Ho u so.“ ocean
zmmocfln com: .UooHn msoflm mo mm H mm .Uooan «Doom ofluoumo mo cowmcmu No

R NQm
.musmmmum «zoom vapoumo

IOonm>s cuwz cowumHoEHum

.musmmmum commsmumm BudwaJ H

.II. hum .

Hoummo

3QO

.mHSmmmum amoumuum Uflfimumhm H mm

was? .3... 2.. 383 oooE Biomass...

QHOEQSU UHHOHMU OH mmaDQmmH .SflQUQflQ DmMmeme .N GHQQE

99

 

 

 

N N

 

 

 

oo.o ww mow oow oww oo wow I o wo
w w ww coo
oo.. wo wow wow wow woo oo www I 0 wow
. w w
mo . ww wow .ow oww oo wow I o wo
w N w ww woo
om.o .o omw oww Iowwl woo oo www I 0 wow
wzoooo¢> mmemw
wo.. ww oww oow wmw woo wow I wo wo
w I w ww woo
.o.o www oow omw mmw woo oo www I 0 wow
. w w
oo o ow mww mmw www oo wow I o wo
w w ww coo
wm.. oow wow www www woo oo wmw I 0 wow
wzoooo<> mmommm
wo 3mm m mo Aozow omewwomwo
mm m m m m mmooxwz wmoewwwezm>
.cws\we ow u sown woomh
monocwn :mmz .ooown mocwm mo mm H mm .Uoown moowm owuowmo mo cowmcmp o
n om .mwommmwm comeMme meocwn H mm .wwommmwm wmwwmuwm owEmumhm H mm

.mwomwmum mocwm Uwpowmo u mum

.mEouomm> Hmwmm pom mwommn UOOwn owcmmowmmms

Iowxoowo awws ooflwwHoEwwm wooqooowoeoxo wmwowwo ow ooooomow swowcmx wowwooq .m oNme

.mwommmwm comeMHmm 3mmpcw£ "33¢

m

.mwommmum mocwm Uwuowmo u mum
.oHSmmmwm wmwwmuwm owEmpmmm H mm
.UOOwQ mocwm mo mm H mm

.oOOHQ mocwm owuowmo mo cowmcmw No n mom

100

.mEouomm> wmumm pom mwomwn UOOHQ owcmmoummmnlowxomwa nuw3 cowumw
ISEwum HoummomHoEozo owuowmo on mmcommmu 3mmocw£ m>wumwcmmmnmmm

 

‘1
«a

Irlmcw

.ow musmwm

101

vm mnsmwm

5.52....
V N O Q N 0 ,Q N o

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

III I «I ..w w w
m . , o w w . I I.I w w m M w M f w w w m Im « m M w w w L m m M u m a .w w w m M H n w m H m _ M w . w M N . ,
w . . I V . . . o
. . . I m, . . . . . w o o m . 4 11L % I . m t . . . w w . n , . m Q I but... .11.. o w . . o . . . ,I I,: 1..I . I lg
. . , . , , ,V
. . . 1 h .7 . . . . . . . . 1. _. o ..., m2; . . . . .. wt, . I L
, _ . , , h
. .. I . I . . . v I .. I ..... I . I I . w o . II I I II
, a o , _ o
,, _ , , . 1 . III, .II.
. a 7 . , . H FIII u . . I
N » Il IIIIIIL _v w
. . w w . , . 1111 I a . . . . .411. I
, 1 114 n
n , . 1 I . . . . .. .II .
i=_l-_ . 1 w ,
. . . .I . 4 I I II. I
, . o
I .w I .9. I . . .III. I I '8“
1. . .I I-.. I. II .. L . . . . III . .I.IIIIII; .. .I
.
I H . I. q. I . 4 ..... I. w . . . w w w w . w , . _ w I .I I . {I It «.11 I. .III I I41 I III 4 I I I . IL . 42.14. 411.
1 . . , I
1 , 1 , . .
. i _ H H , . n , . o .
. , V , . . . .
I , 1 . , _ _, , 1 . _ ,, . . w ,, ,
1 . . . . . . . . , . . . . . . . . . o . .11. .. . i. 3.111. . .. I ,. 1M .III1. 11.11. 1.. ., I. fl .. . ..... .41. a 1?... ...... . I.I. . .q. . . I . I . . . ,. I.1 I III. I
N 1.. . . 1 _ , I 1 I, , n . o _ w _ , H . 1,_, . . , ., I I.. . ., r .
. 1 I . . . . I 1 . . .. . . . . . ... , a _ . , 4 rnr: . .. r . , . w
, . o I . , . , . o o . 4 II I! 1 4 . . ,
, , _ . _ , , , , , . . , . , H ,, , n , H o 1, 1
,V . . . w . . . . .,: .1 .. _., o w . . . . ,. . . . h M ., . . . . h. ,. f .. : .: . h ..1 .. . 7.. . , I .11. . a . . . . 1" . n . 1. #1.. ...: 1,. ..
_ , , I m fl 1M , , . n I . ,, , , 1 I , , _ . , ,, ,
o o . ..... . . . I .u v V ,. . .._ .. . . .. . I ..Iw1. 1“ . . . I o . I . A . . . . . . . .I.I“ . .11
u , . H _ . o u n , , o ,
. ~ " , n a ,. n , , L N
. q . . T . . . I? ... . . . . . I. L . . . I . .I . 1. . . . . . I. .. w I l
. . . _ . . . A ,, . 1 , .
_ . , . . . V . . . , o d . ” w , u _ . .
. . at . . .11. . . . I 1.. . I .1 1..- I. L ...I. . . 1.. . . . , _ . . . . . _ 2.. z..- I . . I . I. I I I LII.EI~I1L
I I .a a _. IuII . u I. I «I . I I .I T......... I . u w :— YIIu.2.124.141.4511 . .1 w I . w: w . . ., I34...IMI...«.IIuII,..11IIIAI . w. ,_ w .7“? A w a . a....¢..II.,... I.II...“ JJIIIIHIIIJIZI
. . , I . _ H u H . w w 1 . . , V 1 n , . . , o W l , , . , .
. . w I . m . . . . . . . . . I. III. . I . . [c
I ,, , . , .
I . . . u . ._ . . . I . . I x I A . I I I
. _ ,
. . . . 3.1. . . ... ......

 

 

 

. . . A .I . . . . I , . . .. . . . .... . I . _.. . . . . .., 1. . . ”1., . ....... . u . . . . Z . I. . .1 . I. .I. . . . . . . . .I . . . . . . I . I “axes”

 

 

 

Mm» 00K . V‘s}...
«« 3. 2 8 «« 8.".oa

2.. «v... «as A

«00930. «00.38 «00.3.8 «0005.?
«0:00. «0.30 U «0.x... «0.5.3 ..
§§h§ >§§h§ >33:

DISCUSSION

Carotid body stimulation by hypoxic-hypercapnic blood
before vagotomy increased vascular resistance in the kidney
but caused no change in resistance in the forelimb, intes-
tine or coronary vasculature (Table 9). After vagotomy,
lrypoxic, hypercapnic and hypoxic—hypercapnic stimulation of
tflne carotid bodies increased vascular resistance in the fore-
llimb, intestine and kidney but not in the heart. Systemic
earterial pressure increased during hypoxic-hypercapnic chemo-
Ineceptor stimulation before vagotomy and increased after
‘lagotomy during stimulation with hypoxia, hypoxic-hypercapnia
iind hypercapnia;- Heart rate was not consistently affected by
<2hemoreceptor stimulation either before or after vagotomy.

This study differs from other investigations of the
Ireflex vascular effects of carotid chemoreceptor stimulation
ii) that selective, physiologic stimuli were applied to the
ilinervated carotid bodies rather than to the entire animal.
Selective stimulation was accomplished by varying the oxygen
iind carbon dioxide tension of autologous blood perfusing the

<2arotid sinuses. This was done by means of an extracorporeal

2 and CO2 gas mixtures. The

uSe of this approach probably results in peripheral responses

ILUng ventilated with various 0

102

103

.AmcoHHm>Hmmno omHHmm How ummu H m.ucm©Dumv mmcmno HCMOHMHcmHm oz:

.AmmUCMHHm> Hmswmcs
cam mcoHum>Hmmno @mHHmmcs How @mHMHUoE ummv u m.H:m©:Hmv mmsam> mmCUHx .m> mo.ouvm

.AmGOHHm>meno cmHHmm How ummu u m.ucmwsumv mo.ouvm«

.mm H mammE mum mmsam>

 

I *v.mH H n.vv «m.m H v.5H +Hm.m H m.m NOU mom I NC mom
I «m.ma H m.bv +¥m.m H H.ma +Ho.v H m.m NOU wm I NO we
I Hm.mH H m.mo «m.ma H m.mm +«o.n H N.HN NOU wow I NC mo

w20900¢> mm5m4 MUZ¢BmHmmm m<ADUm<> 2H m02¢m0 Bzmommm

I «N.HN H 0.0m +o.v H m.v +m.m H m.v NOD mom I NO mo

MZOBOO¢> mmommm mUZ<BmHmmm m¢QDUm<> ZH mOZ<mU Bzmummm

 

Amcsq nmumHOmHv
mumcouoo mmccHx EsmHH QEHHmHom mHDHtz >HOHmHHHGm>

 

 

.weouomm> kumm flaw muomwn GOHHMHSEHHm HoummomHoEmco UHHOHMO mcHst mUmQ
HmHDUmm> mumcouoo cam mmCUHx .EdeH .QEHHwHow CH mocmumflmwu unasomm> CH mmcmco .m mNQma

104

which are more representative of chemoreceptor induced reSpon-
ses in the intact animal than responses evoked by unilateral
carotid sinus perfusion (46), or bilateral perfusion with
heterologous blood (21) or pharmacologic agents (46). The
importance of using a bilateral preparation is suggested by

the work of Sagawa and Watanabe (56) showing that impulses
generated in the left and right carotid sinus nerves during
baroreceptor stimulation summate in the central nervous system.

It is possible that ligation of both internal carotid
arteries in the surgical preparation reduced the blood flow
to the central vasomotor areas (57,58). However, Green and
Rapela (75) reported that because of the extensive collateral
blood supply provided by the vertebral arteries, bilateral
common carotid artery occlusion did not lower vertebral
artery perfusion pressure more than to about 90% of systemic
arterial pressure.

The use of the carotid sinus perfusion circuit containing
an isolated lung has two advantages over procedures previously
employed to determine the effects of carotid body chemorecep-
tor stimulation. First, the method allows the use of auto-
loqous blood and eliminates the necessity of using stagnated
blood or non-physiologic perfusates. Second, it permits rapid
Changes in local blood gas content without detectable changes
in systemic blood gas concentrations. Normal systemic blood
9&8 content is maintained because the blood leaving the sinus

Pelffusion circuit is returned to the animal's venous

105

circulation via the jugular vein. Since the volume of blood
flowing through the perfusion circuit is relatively small,
amounting to less than 5% of the animal's cardiac output,
abnormalities in the 02 and CO2 content of the blood are cor-
rected during passage through the animal's pulmonary circula-
tion.

While many investigators have reported the reflex
responses to carotid chemoreceptor stimulation few studies
have employed selective carotid body stimulation. This makes
a comparison of the data inappropriate since alteration of
the systemic O2 and CO2 blood gas content could produce a
combination of three effects: 1) local vascular effects (60,
62-64), 2) reflex vascular effects due to central nervous sys-
tem chemoreceptor stimulation (4), and 3) reflex effects due
to peripheral arterial chemoreceptor stimulation (4). Of the
few studies in which selective carotid chemoreceptor stimu-
lation was used, most employed pharmacologic or non-physio-
logic rather than physiologic stimuli which also renders a
strict comparison with our findings inappropriate.

The comparison of results is also complicated by the use
of different anesthetics. Some investigators employ chlora-
lose anesthesia (23,40,42,46) while we employed pentobarbital
anesthesia in the present study. Pentobarbital is reported
to depress centrally mediated reflexes while chloralose exag-

gerates these reflexes (52)° Recently, Cox (73,74) compared

the influences of chloralose and pentobarbital anesthesia on

106

cardiovascular function in the dog. The results showed chlora-
lose anesthesia to produce no change in systemic hemodynamics.
The heart rate responses to hypotension and hypertension were
exaggerated. The results showed that the only hemodynamic
effects of pentobarbital anesthesia were a significant increase
in heart rate and slight decrease in stroke volume. Pento-
barbital depressed smooth muscle reactivity and reduced the
sensitivity of the peripheral mechanoreceptor reflexes.

The effects of carotid chemoreceptor stimulation were
studies before and following vagotomy. This was done in order
to determine the role of the carotid chemoreceptors without
the reflex buffering influences of the aortic baroreceptors
and chemoreceptors. Efforts were made to maintain a constant
perfusion pressure in the carotid sinuses to prevent excita-
tion of the carotid sinus baroreceptors.

The rise in vascular resistance, during chemoreceptor
stimulation, observed in the kidney before vagotomy and in
the forelimb, intestine and kidney following vagotomy appears
to be the result of active changes in blood vessel caliber.

An active change is indicated since resistance rose concomi—
tant with an increased transmural pressure which would favor
a passive decrease in vascular resistanceo Increases in
vascular resistance might have been augmented by increases in
blood viscosity via changes in hematocrit subsequent to
splenic discharge. The present findings suggest that carotid

chemoreceptor stimulation results in responses that are

107

mediated over sympathetic nerves with a contribution from
increases in circulating catecholamines. The possibility of
a withdrawal of parasympathetic activity can be ruled out
since only a small proportion of the resistance vessels of the
body receive parasympathetic innervation (70). Therefore, its
effect on total vascular resistance is small. Sympathoadrenal
mediation is indicated by the time course of the response to
chemoreceptor stimulation. The rise in systemic arterial
pressure and organ perfusion pressure concurrent with the
change in blood gas tension, as indicated by the sinus P02,
suggests a neurogenic constrictor response. Frequently, a
distinct secondary rise in pressure was observed. This was
attributed to an increase in circulating catecholamines subse-
quent to adrenal discharge.

The increases in vascular resistance in the forelimb
and intestine following vagotomy were similar in magnitude.
However, the kidney vasculature appeared to be the most re-
sponsive to chemoreceptor stimulation of all of the vascular
beds studied. Haddy and Scott (71) showed a greater sensitiv-
ity in the kidney to the systemic administration of epine-
phrine and norepinephrine than in the intestine or hindlimb.
The greater responsiveness of the kidney could be related to
an augmenting pressor action of angiotension subsequent to the
release of renin. Vander (72) reported direct electrical

Stimulation of renal nerves and intravenous infusions of

108

norepinephrine and epinephrine, while keeping aortic pressure
constant, to increase renin release from the kidney.

The responses evoked from the forelimb, kidney and intes-
tinal vasculature during carotid chemoreceptor stimulation
are directionally similar to the responses induced by carotid
sinus hypotension. In the present study, a 30% increase in
renal vascular resistance was produced when carotid sinus
perfusion pressure was reduced from 102 to 47 mm Hg. Similar-
ly, Fronek (65) reported increased mesenteric artery re-
sistance during carotid sinus hypotension. DiSalvo et al.
(59) reported increases in forelimb skin (56%) and muscle
(31%) vascular resistances when perfusion pressure in the_
isolated carotid sinuses was reduced from 108 to 59 mm Hg.

Brachial and cephalic venous outflows in the forelimb
study,twhere total limb inflow was constant, showed no change
from control during chemoreceptor stimulation. The absence
of a change in brachial and cephalic venous outflows during
the increase in forelimb vascular resistance indicates that
the muscle and skin vascular beds contributed about equally
to the increase in forelimb resistance. Calvelo gt El-
reported increased vascular resistance in the gracilis muscle
during carotid chemoreceptor stimulation with nicotine and
cyanide. However, they reported that chemoreceptor stimula-
tion induced vasodilation in the hindpaw (skin) that was
unchanged or augmented by pharmacologic alpha blockade. This

response in the skin vasculature is different from the results

109

obtained in the present work in which only constriction was
seen. These differences could be explained if we failed to
separate the skin and muscle in the forelimb. To test this
possibility we employed an isolated skin and muscle prepara-
tion in the hindlimb similar to that used by Calvelo gt 3l°
(23). The results of these preliminary studies confirmed the
vasoconstriction in skin. The discrepancy in these reports
has yet to be resolved and could possibly be related to the
anesthesia employed, that is, pentobarbital versus chlora-
lose.l
The responses of the coronary vasculature to carotid
chemoreceptor stimulation were investigated in two studies.
One study examined the responses to stimulation with the
hypoxic, hypoxic-hypercapnic and hypercapnic stimuli employed
in the previous studies on the forelimb, intestine and
kidney. The second study examined the reSponses of the coro-
nary vasculature to chemoreceptor stimulation with blood that
was less hypoxic, less hypoxic-hypercapnic or less hypercapnic
than was employed in the first study. Carotid chemoreceptor
stimulation before and following vagotomy produced no consis-
tent changes in coronary vascular resistance. Hackett gt El.

(46) recently reported reflex coronary vasodilation during

 

1In one experiment, using the same hindpaw preparation
and anesthetic as that employed by_Calvelo gt El° we again
observed vasoconstriction in skin during chemoreceptor stimula-
tion.

110

carotid chemoreceptor stimulation with nicotine and cyanide,
and during carotid sinus nerve stimulation. Ventricular
pacing and AY-21,011 (a myocardio-selective beta-receptor
antagonist) were used to minimize the chronotrOpic and ino-
tr0pic responses to chemoreceptor stimulation. They reported
that the intravenous administration of atropine blocked the
reflex coronary dilator response and proposed the efferent
pathway mediating the response to be through vagal cholinergic
fibers. This difference in findings might be attributable to
a differing response to physiologic versus pharmacologic
chemoreceptor stimulation. DiSalvo 32 El. (61) reported no
change in coronary vascular resistance in a natural flow coro-
nary preparation when pressure in the isolated carotid sinuses
was lowered from 87 to 48 mm Hg.

Since our data indicate no consistent change in coronary
vascular resistance during carotid body stimulation concomi-
tant with a fall in left ventricular contractile force, it
appears that factors which produce vasoconstriction acted along
with those producing vasodilation. The factors favoring vaso-
constriction in this constant coronary blood flow preparation
include 1) a decreased vasodilator metabolite concentration
due to a fall in heart metabolism as indicated by the fall in
ventricular contractile force (62) (the change in contractile
force will be discussed in detail later), 2) a myogenic vaso-
constriction (Bayliss effect) in response to an increased

transmural pressure resulting from a fall in extravascular

lll

pressure subsequent to a decrease in contractile force (66,
67), and 3) a decreased sympathetic tone to the heart (66).
The factors favoring vasodilation include 1) an increase in
circulating catecholamines and 2) a passive increase in
vessel caliber due to a falluin extravascular pressure result-
ing from a decreased ventricular contractile force. The lack
of a response in coronary resistance suggests that the above
factors balance out to produce no net change.

The decrease in left ventricular contractile force ob-
served during chemoreceptor stimulation was greater following
vagotomy than before. DeGeest gt il’ (48) reported that
hypoxic chemoreceptor stimulation before vagotomy diminished
left ventricular contractile force in the paced, isovolu-
metric heart. However, they found the negative inotrOpic
effect elicited by chemoreceptor stimulation to be abolished
by cervical vagotomy suggesting mediation mainly by vagal
pathways. Downing et_al. (43) have also reported a decreased
left ventricular contractility during hypoxic carotid chemo—
receptor stimulation following vagotomy, however, these
investigators did not study contractility before vagotomy.
These investigators suggest the diSparity in findings to be
due to possible differences in the magnitude of concomitant
excitation of the respiratory and vasomotor centers during
chemoreceptor stimulation. They reported that, after vagotomy,

it is likely that a diminution of sympathetic tone represents

112

the primary cardiac reflex effect of carotid chemoreceptor
stimulation. Excitation of the respiratory centers resulting
from chemoreceptor stimulation also tends to increase cardiac
sympathetic activity thus producing a secondary cardiac ef-
fect. They conclude that in some cases the secondary cardiac
effects due to reSpiratory center excitation may predominate
over the primary cardiac effect of chemoreceptor stimulation.
Hackett gt El° (61) reported an increase in left ventricular
dP/dt during unilateral carotid chemoreceptor stimulation
with nicotine and cyanide before and after vagotomy. This
difference in findings might again be attributable to a dif-
fering response to physiologic versus pharmacologic chemo-
receptor stimulation.

While the data from these studies indicate a sympatho-
adrenal mediated vasoconstriction in the peripheral vascula-
ture, the results indicate a concomitant selective diminution
of sympathetic tone to the heart.

Mechanical factors in the heart could have contributed
to the decrease in ventricular contractile force produced by
carotid chemoreceptor stimulation. A diminished cardiac
sympathetic tone could have been augmented by an increase in
afterload of the heart since systemic pressure increased as
contractile force fell.

Heart rate was measured during chemoreceptor stimulation
before and after vagotomy in all experiments. The data indi-

cated no consistent changes in heart rate during chemoreceptor

113

stimulation with any of the experimental gas miXtures.

These results differ from the findings of many investigators
(39,40-43),48) using a similar preparation with controlled
ventilation. When respiration is controlled, carotid chemo-
receptor stimulation produced bradycardia. Daly and Scott
(40) and Downing (42) prOposed that the primary reflex effect
of carotid chemoreceptor stimulation on heart rate is a
vagally induced bradycardia. This reflex bradycardia can

be over-ridden by secondary mechanisms evoked by concomitant
increases in respiration, changes in arterial pressure and
circulating catecholamines (40,42,55). Since we held ventil-
atory rate and volume constant our findings on heart rate
could be due to the type of anesthetic employed. Daly and
Scott (40) and Downing (42) used chloralose anesthesia while
our work was carried out with pentobarbital.

Carotid chemoreceptor stimulation with combined hypoxia
and hypercapnia following vagotomy caused a greater increase
in forelimb, intestine and kidney vascular resistance than
was produced by hypoxia or hypercapnia alone (Table 9).
Hypoxia-hypercapnic blood caused a 26% increase in forelimb
vascular resistance while hypoxic or hypercapnic blood alone
increased resistance by 12% and 11%, respectively. Before
vagotomy, hypoxic-hypercapnic chemoreceptor stimulation in-
creased renal vascular resistance by 56%. Following vagotomy,
hypoxic-hypercapnic stimulation caused a 69% increase in renal

resistance, while hypoxia and hypercapnia alone increased

114

resistance by 48% and 45%, respectively. Similarly, combined
hypoxic-hypercapnic chemoreceptor stimulation caused a 33%
increase in ileal vascular resistance, while hypoxia alone
increased resistance by 13% and hypercapnia increased
resistance by 17%.

The rise in systemic arterial pressure during carotid
chemoreceptor stimulation may have resulted either from an
increase in total peripheral resistance or cardiac output or
a combination of both. Since cardiac output was not measured
in this study it was not possible to determine total peri-
pheral resistance. The reflex buffering effect produced by
the aortic baro- and chemoreceptors probably attenuated the
rise in systemic pressure before vagotomy. Although intes-
tinal, skin and muscle vascular resistance was unchanged
during chemoreceptor stimulation before vagotomy, kidney re-
sistance was markedly elevated. Increases in resistance in
other vascular beds which were not measured may also have con-
tributed to a rise in total peripheral resistance. Following
vagotomy, a rise in resistance in the intestine, kidney,
skin and muscle also contributes to the rise in peripheral

resistance during chemoreceptor stimulation.

SUMMARY AND CONCLUSIONS

The purpose of this study was to determine the reflex
effects of selective, physiologic stimulation of the carotid
body chemoreceptors on the vascular resistance of the fore-
limb, kidney, intestine and heart. Selective physiologic
chemoreceptor stimulation was accomplished by varying the gas
content of autologous blood perfusing the isolated carotid
sinuses by means of an extracorporeal lung ventilated with
various O2 and CO2 gas mixtures.

The reflex responses to carotid chemoreceptor stimula-
tion were studied in the dog before and following vagotomy.
Systemic arterial pressure increased during chemoreceptor
stimulation with hypoxic-hypercapnic blood before vagotomy.
Following vagotomy, systemic pressure increased during carotid
body stimulation with hypoxic, hypoxic-hypercapnic and hyper-
capnic blood. Carotid chemoreceptor stimulation with hypoxic-
hypercapnic blood before vagotomy increased vascular
resistance in the kidney but caused no change in resistance in
the forelimb, intestine or coronary vasculature. After vagot-
omy, hypoxic, hypoxic-hypercapnic and hypercapnic chemoreceptor
stimulation increased vascular resistance in the forelimb,

intestine and kidney but not in the heart.

115

116

During hypoxic-hypercapnic chemoreceptor stimulation
following vagotomy vascular resistance in the kidney in-
creased 69% while forelimb and ileal resistance increased
26% and 33%, respectively. The absence of a change in
skeletal muscle and skin blood flow in the forelimb prepara-
tion indicated that the skin and muscle vascular beds
contributed about equally to the increase in forelimb resis-

tance. To further examine the effects of chemoreceptor

 

stimulation on the skin and skeletal muscle vasculature a . I .
gracilis muscle and hindpaw preparation was employed. The E—j
results of these preliminary studies indicated vasoconstric-
tion in muscle and skin during hypoxic-hypercapnic chemo-
receptor stimulation.
The rise in vascular resistance observed in the kidney
before vagotomy and in the forelimb, intestine and kidney
following vagotomy appeared to be the result of active changes
in blood vessel caliber. The responses appear to be mediated
over sympathetic nerves with a contribution from increased
circulating catecholamines.
Changes in left ventricular contractile force during
chemoreceptor stimulation were measured in a heart preparation
having a constant coronary blood flow. Left ventricular
contractile force decreased during chemoreceptor stimulation
before and after vagotomy but larger reductions in contractile
force were observed following vagotomy. The decrease in

contractile force appears to be primarily the result of a

117

diminished sympathetic tone to the heart possibly augmented
by an increased afterload. Heart rate was not consistently
affected by chemoreceptor stimulation either before or
following vagotomy.

These studies suggest that carotid body chemoreceptor

stimulation increases systemic arterial pressure in part by

In-ULL
- I . '
-—.

increasing total peripheral resistance. The studies also
indicate that hypoxia and hypercapnia act on the carotid body

chemoreceptors to elicit changes in autonomic outflow to the

 

vasculature similar to changes induced by lowering the pres-

sure in the carotid sinuses.

BIBLIOGRAPHY

10.

BIBLIOGRAPHY

Chungcharoen, D., M. deB. Daly, and A. Schweitzer. The
blood supply of the carotid body in cats, dogs, and
rabbits. J. Physiol. (London) 117:347, 1952.

DeCastro, F. Sur la structure de la synapse dans 1es
chemorecepteurs: leur mechanisme d'excitation at role
dans la arculation sanguine locale. Acta Physiol.
Scand. 22:14, 1951.

Daly, M. deB., C. J. Lambertsen and A. Schweitzer.
Observations of the volume of blood flow and oxygen
utilization of the carotid body of the cat. J. Physiol.
(London) 125:67, 1954.

Heymans, C., and E. Neil. Reflexogenic Areas of the
Cardiovascular System. London, Churchill, 1958.

Biscoe, T. J., M. J. Purves, and S. R. Sampson. The
frequency of nerve impulses in single carotid body
~qhemoreceptor afferent fibers recorded in vivo with
intact circulation. J. Physiol. (LondoHT 208:121-131,
1970.

Eyzaguirre, C. and J. Lewin. Effect of different oxygen
tensions on the carotid body in vitro. J. Physiol.
(London) 159:238-250, 1961.

Landgren, S. and E. Neil. Chemoreceptor impulse activity
following hemorrhage. Acta Physiol. Scand. 23:158-167,
1951.

Hornbein, T. F., The relation between stimulus to chemo-
receptors and their responses. In: Arterial Chemo—
receptors, edited by R. W. Torrance. Oxford, Blackwell
Scientific publications, 1968.

Duke, H. N., J. H. Green and E. Neil. Carotid chemo-
receptor activity during inhalation of carbon monoxide
mixtures. J. Physiol. (London) 118:520-527, 1952.

Comroe, J. H. Physiology of ReSpiration. Chicago,
Year Book Medical Publishers Incorporated, 1969.

118

 

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

119

Comroe, J. H. and C. F. Schmidt. The part played by
reflexes from the carotid body in the chemical regula-
tion of reSpiration in the dog. Am. J. Physiol.
121:75-79, 1938.

Eyzaguirre, C. and J. Lewin. Chemoreceptor activity of
the carotid body of the cat. J. Physiol. (London)
159:222-237, 1961.

Eyzaguirre, C. and J. Lewin. Effect of different oxygen
tensions on the carotid body in vitro. J. Physiol.
(London) 159:238-250, 1961.

Biscoe, T. J. and R. A. Millar. Inhalation anaesthetics
and systemic chemoreceptor activity. J. Physiol.
(London) 182:24P, 1966.

Hornbein, T. F. and A. Roos. Specificity of H ion con-
centration as a carotid chemoreceptor stimulus.
J. Appl. Physiol. 18:580-584, 1963.

Joels, N. and E. Neil. Chemoreceptor impulse activity
evoked by perfusion of the glomus at various FCC
and pH values. J. Physiol. (London) 154:7P, 1968.

Eyzaguirre, C. and H. Koyano. Effects of hypoxia, hyper-
capnia, and pH on the chemoreceptor activity of the
carotid body in vitro. J. Physiol. (London) 178:
385-409, 1965.

 

Gray, B. A. Response of the perfused carotid body to
changes in pH and P . Resp. Physiol. 4:229-245,
1968 C02

McCloskey, D. I. Carbon dioxide and the carotid body.
In: Arterial Chemoreceptors, Edited by R. W. Torrance.
Oxford, Blackwell Scientific Publications, 1968.

Travis, D. M. Molecular C02 is inert on carotid chemo-
receptor: Demonstration by inhibition of carbonic
anhydrase. J. Pharm and Exptl Ther. 178:529, 1971.

Pelletier, C. L. and J. T. Shepherd. Venous responses
to stimulation of carotid chemoreceptors by hypoxia
and hypercapnia. Am. J. Physiol. 223:97-103, 1972.

Biscoe, T. J. Carotid body: structure and function.
Physiol. Rev. 51:437-495, 1971.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

120

Calvelo, M. G., F. M. Abboud, D. R. Ballard and W. Abdel-
Sayed. Reflex vascular responses to stimulation of
chemoreceptors with nicotine and cyanide. Circ. Res.
27:259-276, 1970.

Bernthal, T. and F. J. Schwind. A comparison in intes-
tine and leg of the reflex vascular response to
carotid-aortic chemoreceptor stimulation. Am. J. Physiol.
143:361-372, 1945.

Winder, C. V., T. Bernthal and W. F. Weeks. Reflex f‘**
hyperpnea and vasoconstriction due to ischemic excita-
tion of the carotid body. Am. J. Physiol. 124:238-
245, 1938.

 

Korner, P. I. and J. B. Uther. Dynamic characteristics
of the cardiovascular autonomic effects during severe
arterial hypoxia in the unanesthetized rabbit. Circ.
Res. 24:671, 1969.

 

Jacobs, L., S. R. Sampson and J. H. Comroe, Jr. Carotid
sinus versus carotid body origin of nicotine and
cyanide bradycardia in the dog. Am. J. Physiol. 220:
472-476, 1971.

Bernthal, T. Chemo-reflex control of vascular reactions
through the carotid body. Am. J. Physiol. 121:1-20,
1938.

Bernthal, T., H. F. Motley, F. J. Schwind and W. F.
Weeks. The efferent pathway of chemoreflex vasomotor
reactions arising from the carotid body. Am. J.
Physiol. 143:220-225, 1945.

Litwin, J., A. H. Dil, and D. M. Aviado. Effects of
anoxia on the vascular resistance of the dog's hind-
limb. Circ. Res. 8:585-593, 1960.

Comroe, J. H., Jr., and L. Mortimer. The reSpiratory
and cardiovascular responses to temporally separated
aortic and carotid bodies to cyanide, nicotine,
phenyldiguanide and serotonin. J. Pharm. Exptl. Ther.
146:33, 1964.

Caldwell, F. T., D. Rolf and H. L. White. Effects of
acute hypoxia on the renal circulation in man. J. Appl.
Physiol. 1:597, 1949.

Franklin, K. J., L. E. McGee and E. A. Ullman. Effects
of severe asphyxia on the kidney and urine flow.
J. Physiol. (London) 112:43, 1951.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

121

Korner, P. I. Effects of low oxygen and of carbon
monoxide on the renal circulation in unanesthetized
rabbits. Circ. Res. 12:361-374, 1963.

Von Euler, U. S. and G. Liljestrand. Influence of
oxygen inhalation on the chemoreceptor activity of
the sinus region. Acta Physiol. Scand. 4:34-44,
1942.

Whitehorn, W. V., A. Edelmann and F. A. Hitchcock. The
cardiovascular responses to the breathing of 100 per
cent oxygen at normal barometric pressure. Am. J.
Physiol. 146:61-65, 1946.

Dripps, R. D. and J. H. Comroe. The effect of the
inhalation of high and low oxygen concentrations on
respiration, pulse rate, ballistocardiogram and
arterial oxygen saturation (oximeter) of normal
individuals. Am. J. Physiol. 149:277-291, 1947.

Alveryd, A. and S. Brody. Cardiovascular and respira-
tory changes in man during oxygen breathing. Acta
Physiol. Scand. 15:140-149, 1948.

Bernthal, T., W. Greene and A. M. Revzin. Role of
carotid chemoreceptors in hypoxic cardiac acceleration.
Proc. Soc. Exp. Biol. Med. 76:121, 1951.

Daly, M. deB., and M. J. Scott. The effects of stimula-
tion of the carotid body chemoreceptors on the heart
rate of the dog. J. Physiol. (London) 144:148-166,
1958.

Daly, M. deB. and M. J. Scott. Role of the chemorecep-
tors in the cardiovascular responses to systemic hypoxia
in the dog. J. Physiol. (London) 154:6P, 1960.

Daly, M. deB. and M. J. Scott. An analysis of the primary
reflex effects of stimulation of the carotid body chemo-
receptors in the dog. J. Physiol. (London) 162:555-573,
1962.

Downing, S. E., J. P. Remensnyder and J. H. Mitchell.
Cardiovascular responses to hypoxic stimulation of the
carotid bodies. Circ. Res. 10:676, 1962.

Stern, S. and E. Rapaport. Comparison of the reflexes
elicited from combined or separate stimulation of aortic
and carotid chemoreceptors on myocardial contractility,
cardiac output and systemic resistance. Circ. Res.
20:214-227, 1967.

45.

46.

47.

48.

49.

50.

51.

52.

54.

55.

56.

57.

122

Vatner, S. F., D. Franklin, R. L. VanCitters and E.
Braunwald. Effects of carotid sinus nerve stimulation
on the coronary circulation of the conscious dog.
Circ. Res. 27:11-21, 1970.

Hackett, J. G., F. M. Abboud, A. L. Mark, P. G. Schmid
and D. D. Heistad. Coronary vascular responses to
stimulation of chemoreceptors and baroreceptors.
Circ. Res. 31:8-17, 1972.

Krasney, J. A. Regional circulatory responses to
arterial hypoxia in the anesthetized dog. Am. J. Physiol.
220:699-704, 1971.

DeGeest, H., M. N. Levy and H. Zieske. Carotid chemo-
receptor stimulation and ventricular performance.
Am. J. Physiol. 209:564-570, 1965.

Downing, S. E. Neural regulation of circulation during
hypoxia and acidosis with special reference to the
newborn. Fed. Proc. 3:1209-1218, 1972.

Joels, N., and M. Samueloff. The activity of the medul-
lary centres in diffusion respiration. J. Physiol.
London 133:360-372, 1956.

Imperial, E. S., M. N. Levy and H. Zieske. Outflow
resistance as an independent determinant of cardiac
performance. Circ. Res. 9:1148-1154, 1961.

DiPalma, J. R., editor. Drill's Pharmacology in Medicine.
McGraw-Hill, New York, 1965.

Salem, H., M. Penna and D. M. Aviado. Mechanism for
bradycardia arising from stimulation of the carotid
bodies. Arch. Intern. Pharmacodyn. 150:249-258, 1964.

Anitchkov, S. V., E. I. Malyghina, A. N. Poskalenko and
V. E. Ryzhenkov. Reflexes from the carotid bodies
upon the adrenals. Arch. Intern. Pharmacodyn. 129:
156-165, 1960.

Sagawa, K. and K. Watanabe. Summation of bilateral
carotid sinus signals in the barostatis reflex. Am.
J. Physiol. 209:1278-1280, 1965.

Milnor, W. R. Blood supply of special regions. In:
Medical Physiology, edited by V. B. Mountcastle.
Mosby, St. Louis, 1968, Vol. I, pp. 221-227.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

123

Miller, M. E., G. C. Christensen, and H. E. Evans.

Anatomy of the dog. W. B. Saunders Co., Philadelphia,
1968.

DiSalvo, J., P. E. Parker, J. B. Scott and F. J. Haddy.
Carotid baroreceptor influence on total and segmental
resistances in skin and muscle vasculatures. Am. J.
Physiol. 220:1970-1978, 1971.

Daugherty, R. M., Jr., J. B. Scott and F. J. Haddy.
Effects of generalized hypoxemia and hypercapnia on
forelimb vascular resistance. Am. J. Physiol. 213:
1111-1114, 1967.

DiSalvo, J., P. E. Parker, J. B. Scott and F. J. Haddy.
Carotid baroreceptor influence on coronary vascular
resistance in the anesthetized dog. Am. J. Physiol.
221:156—160, 1971.

Haddy, F. J. and J. B. Scott. Metabolically linked
vasoactive chemicals in local regulation of blood flow.
Physiol. Rev. 48:688-707, 1968.

Scott, J. B., R. M. Daugherty, Jr., J. M. Dabney and
F. J. Haddy. Role of chemical factors in regulation
of flow through kidney, hindlimb and heart. Am. J.
Physiol. 208:813-824, 1965.

Daugherty, R. M., Jr., J. B. Scott, J. M. Dabney and
F. J. Haddy. Local effects of O and CO2 on limb,
renal, and coronary vascular resistances. Am. J.

Physiol. 1102-1110, 1967.

Fronek, A. Combined effect of carotid sinus hypotension
and digestion on splanchnic circulation. Am. J.
Physiol. 219:1759-1762, 1970.

Berne, R. M. Regulation of coronary blood flow. Physiol.
Rev. 44:1-29, 1964.

Mellander, S. Systemic circulation: local control.
Ann. Rev. Med. 32:313-344, 1970.

Daugherty, R. M., Jr., J. B. Scott, T. E. Emerson, Jr.,
and F. J. Haddy. Comparison of iv and ia infusion of
vasoactive agents on dog forelimb blood flow. Am. J.
Physiol. 214:611-619, 1968.

Steel, R. G. D. and J. H. Torrie. Principles and
Procedures of Statistics with Special Reference to
Biological Sciences. McGraw-Hill, New York, 1960.

70.

71.

72.

73.

74.

75.

124

Berne, R. M. and M. N. Levy. Cardiovascular Physiology.
Mosby, St. Louis, 1972.

Haddy, F. J. and J. B. Scott. Cardiovascular pharma—
cology. Ann. Rev. Pharm. 6:49-76, 1966.

Vander, A. J. Effects of catecholamines and the renal
nerves on renin secretion in anesthetized dogs. Am. J.
Physiol. 209:659, 1965.

Cox, R. H. Influence of pentobarbital anesthesia on r
cardiovascular function in trained dogs. Am. J.
Physiol. 223:651-659, 1972.

”Mai-1'2" L'fl

Cox, R. H. Influence of chloralose anesthesia on
cardiovascular function in trained dogs. Am. J.
Physiol. 223:660-667, 1972.

 

Green, H. D. and C. E. Rapela. Cerebral vascular response
to localized and systemic hypotension induced by hemor-
rhage and shock. In: Microcirculation as Related to
Shock. Academic Press, New York, 1968.

APPENDICES

APPENDIX A

RAW DATA

125

126

LIST OF ABBREVIATIONS

(For APPENDIX A)

PCS = carotid sinus pressure (mm Hg)

PS = systemic arterial pressure (mm Hg)

PBA = brachial artery pressure (mm Hg)

PMA = mesenteric artery or ileal segment perfusion pressure
(mm Hg)

PSMA = superior mesenteric artery pressure (mm Hg)

PR = renal artery pressure (mm Hg)

CSP = carotid sinus pressure (mm Hg)

FBV = brachial vein blood flow (ml/min)

FCV = cephalic vein blood flow (ml/min)

FMA = mesenteric artery blood flow (ml/min)

FSMA = superior mesenteric artery blod flow (ml/min)
FR = renal artery blood flow (ml/min)

HR = heart rate (beats/min)

P02 = 02 tension of the carotid sinus blood (mm Hg)
pH = pH of the carotid sinus blood

M

t a = ileal segment intraluminal pressure (mm Hg), t and a
are qualitative assessments of ileal tone and activity,

respectively, (scale: 0 - 4)

127

mm.h

vw.h
No.5
mm.b
mm.h
mm.h
mm.b
om.h
vm.>
Om.>
om.h

mm

mHH

OOH
NOH
NNH
OOH
ONH
ONH
NOH
OO.
OHH
mm

HOH

va
HON
vOH
NOH
OOH
OOH
VOH
ONH
mmH
NOH

mm

w.om
0.0m
N.H
O.Hm
0.00
0.0v
0.0H
0.0h
0.0v
0.00
>0

H.Hm OHH
0.0v NNH
0.0v OVH
~.hv OOH
0.0m OHH
0.0m OO
0.0v VO
O.NO va
0.0m nHH
0.0V OO
0.0v OOH
>mm dmm
wEouomm>mHm
HH¢ Eoom

NNH

OOH
va
OOH
OOH
ONH
OHH
ONH
OOH
hOH
mHH

ONH

NOH
OOH
ONH
NVH
mNH
OHH
ONH
HNH
mHH
OHH

mu

Om.n

mm.h
mm.h
Om.h
mm.h
mm.h
mN.h
Hm.b
hm.h

.5N.h

nm.n
ma

OHH

mNH
ONH
NHH
OOH
OOH
hNH
OOH
OOH
OHH
Ow

mZHHmmom

th

th
OHN
NOH
HNH
ONH
NOH
OOH
OOH
OOH
NOH

mm

s.mv m.om mHH mMH
v.om «.mv mMH VMH
w.nm m.mv an mmH
O.H ¢.mv omH OHH
w.mm 0.4m OHH mmH
n.sm 0.0m om emH
o.ov o.mv mm OHH
m.sH ¢.om va NNH
m.He o.vm omH mmH
0.0v o.vv mm OHH
o.on 0.0v OHH omH

>0m >mm «mm mm

OEOHomm>mHm

AHonucooO Noo mm I No

NNH

ONH
OOH
mmH
OOH
NNH
OOH
ONH
ONH
ONH
OHH

m0

OON

cmmz

H

HNMVLOle‘CDONO

# moo

128

00.0 00 450 0.04 0.00 400 H00 H00 00.5 000 050 5.04 0.00 000 000 50H :00:
00.5 4H 00H 0.00 0.54 00H 04H 00H 00.5 000 540 4.00 4.04 00H 40H 00H 0H
00.0 40 000 0.00 0.44 000 000 04H 00.5 000 000 0.50 0.04 500 00H 00H 0
00.0 00 04H 4.4 0.04 00H 45H 00H 00.5 500 000 0.4 4.04 000 040 00H 0
40.5 00 05H 0.50 0.00 000 00H 000 00.5 000 H50 0.00 0.40 000 000 000 5
00.0 00 H50 0.05 0.00 00 40H 000 00.5 000 45H 5.50 0.00 00 50H 00H 0
00.0 HH 000 4.04 0.00 50 000 00H 00.5 500 000 0.04 0.04 00 000 000 0
50.0 00 000 0.00 0.00 004 050 000 00.5 00H 000 0.50 4.00 40H 00H 00H 4
00.0 00 00H 0.50 0.00 000 000 000 50.5 00H 000 0.05 0.40 000 00H 00H 0
00.0 00 00H 0.04 0.04 000 000 000 50.5 000 000 0.04 0.44 00 000 000 0
00.5 50 050 0.05 0.04 400 000 0H0 50.5 00 000 0.05 0.04 000 000 00H H

mm 000 mm >o0 >00 0mm mm mom mm 000 mm >o0 >mm 000 mm mom 0 moo.

Hzosoo<>mmm HzoeooH>mmm
00o 000 I 0o 00 Aaonucoov 00o 00 u 0o 000

mSHHmmom

129

HO.h

OO.h
H0.0
HO.>
O0.0
HO.h
ON.b
OO.h
OO.>
ON.h
OO.n

mm

OH

HH
NH

OH
OH

OH
ON
NH
ON

OOH

OOH
HON
OOH
HOH
OOH
OON
NOH
OhH
NOH
OOH

mm

O.HO
0.00
0.0

O.wO
O.Nh
0.00
0.0H
O.Nh
0.00
O.Nm

>U

N

0.00 000
0.04 000
0.04 000
0.04 000
0.00 000
0.00 05
0.04 50
0.00 040
0.00 500
0.44 000
0.04 000
>00 000
wzosou<>000
oo 00 I 0o 00

OOH

OOH
HOH
OOH
OOH
OOH
OOH
HOH
OOH
OOH
HO

«-

NNH

ONH
HOH
OOH
OOH
OHH
OHH
NHH
NHH
OHH
OHH

mu

ON.O

OO.b
ON.h
O0.0
NO.h
ON.h
NN.h
HO.>
ON.h
ON.>
0N.h

mm

OHH

ONH
ONH
OHH
ONH
HOH
OHH
OOH
OOH
OHH
OO

mZHHmmom

OOH

NOH
ONN
OOH
HOH
OOH
OOH
OOH
OOH
OOH
NOH

mm

0.00 0.00 000 000
0.00 0.54 50H 000
0.00 0.04 040 000
0.0 4.04 050 50H
0.00 0.00 000 00H
O.H5 0.00 05 NOH
0.04 0.04 00 00H
0.0H 0.05 04H 00H
0.05 0.00 50H 00H
0.04 0.44 00H OHH
0.05 0.44 NHH OHH
>o0 >00 000 00

HzoaooO>000
AHoyucoov oo 00 I 0

ONH

OOH
OOH
HOH
OOH
ONH
OHH
NNH
NNH
OHH
OHH

m0

OON

:00:

H

HvamkohmmO

O Ooo

130

 

00.0 000 050 4.00 0.04 000 500 000 00.5 000 050 0.00 0.04 400 000 500 :00:
00.0 040 040 0.00 0.54 000 000 000 00.5 000 040 0.00 0.54 000 500 000 00
00.0 040 000 0.00 0.50 040 000 040 00.5 000 000 0.00 0.00 000 000 040 0
00.0 500 000 0.00 0.00 000 000 000 00.5 000 000 0.0 0.00 000 000 000 0
00.0 000 000 0.00 0.00 400 400 040 00.5 000 000 4.00 0.00 400 050 000 5
00.0 440 000 0.05 0.40 55 000 400 00.5 000 400 0.05 0.00 05 000 000 0
00.0 400 000 0.04 0.04 00 000 000 00.5 000 000 0.04 0.04 40 00 000 0
50.0 000 000 0.00 0.00 000 400 000 00.5 50 000 0.00 4.00 000 000 000 4
00.0 400 050 0.40 0.00 000 040 000 00.5 000 050 5.05 0.40 000 400 400 0
O0.0 OOH OOH 0.00 0.00 ONH OOH OHH mm.h OHH OOH 0.00 0.00 OHH OOH OHH N
00.5 00 050 0.00 0.44 000 50 400 50.5 50 000 4.05 0.44 000 000 000 0

00 000 00 >o0 >00 000 00 0o0 00 0o0 00 >00 >00 000 00 000 0 moo

wzoaooa>000 Hzosood>000
0oo 000 I 0o 000 000000000 0oo 00 I 0o 000

mEHHmmom

131

OH

NN
ON
HN
HH
NH
OH
ON
ON
HH
OH
NN
OH
ON

OOH

OOH
OOH
OOH
OOH
OOH
OOH
OOH

OOH
OOH
OOH
OOH

mm

 

r» EEO"—

0.00 H.OO OOH OOH OHH 00.5 OHH OOH 0.00 0.00 OHH OHH OHH

I I OOH OOH OHH 00.5 OHH I I I OOH OHH OHH
0.00 0.00 OHH ONH OHH O0.0 OHH ONH 0.05 0.00 OOH OOH OHH
0.0NH 0.00 OO OOH OOH 00.0 HOH OOH 0.0HH 0.00 OO OOH HOH
0.00 0.00 ONH OOH NOH I ONH ONH N.0O N.OO ONH OOH OOH
0.00 0.00 OOH OHH NHH 00.5 ONH OON H.OO 0.00 OOH OOH HHH
0.0H 0.0m 05H OOH H00 I OOH OOH N.0H 0.0N O5H ONH OHH
O.HO 0.00 OHH OOH OOH I OOH OOH 0.00 0.00 OOH OOH NOH
0.05 0.00 OHH 05H NNH 00.5 OHH OOH 0.00 0.00 00 OHH ONH
0.00 0.00 OOH ONH O5 00.0 00H OOH 0.00 0.00 00 O0 Oh
0.0H 0.00 50H OOH OOH I NOH OOH 0.0H 0.00 OOH OOH OOH
0.00 0.00 OOH 05H OHH I OOH NOH 0.00 0.00 ONH HOH HNH
0.00 0.00 00H OOH OO I ONH OOH 0.00 0.00 HOH 00 00
0.00 0.00 OOH ONH OHH 50.0 OOH OOH O.HO N.OO OO HO OO
>o0 >00 000 00 0o0 00 000 00 >o0 >00 000 00 000

OEOBOO<>BOOO

NZOBOU<>BOOO

NOU OON I No OO AHOHucooO 000 OO I NC OON

mZHHmmom

C602

I—INM
I—IHI—i

HNMV‘IDKDFQDQO
H

O O00

132

ON.O

ON.O
O0.0
ON.O
ON.O
H0.0
ON.O
O0.0
O0.0
OH.O
ON.O
ON.O
ON.O

mm

OH

OH
ON
OH

HH

ON
OH

OH
OH
OH
ON

OOH

OOH
OOH
NOH
NOH
OOH
OOH
OOH
NOH
OOH
OOH
OOH
OOH

mm

 

r. -Iua
0.50 0.44 000 500

I I 000 000
0.00 0.44 000 000
0.400 0.00 50 000
0.00 0.00, 000 040
0.00 0.04 040 00
0.00 4.00 000 400
0.00 0.00 500 040
0.05 0.50 000 040
0.04 0.04 400 00
0.00 0.44 050 000
0.00 0.44 000 040
0.04 0.00 000 040
0.55 0.44 000 000
>o0 >00 000 00

0200000>0000

0oo 00 I 0o 00

OHH

OOH
OHH
OOH
OOH
OOH
OOH
OOH
ONH
OO

OOH
OHH
OO

OO

m0

ON.O OHH
I NHH
O0.0 OOH
ON.O HO
ON.O OHH
ON.O OHH
ON.O OOH
ON.O ONH
ON.O ONH
ON.O OHH
I OO
ON.O OOH
ON.O OHH
I OHH
mm Nom

mSHHmmom

OOH

OOH
OOH
ONH
OON
OOH
OOH
OOH
OOH
OOH
OOH
OOH
OOH

mm

H.OO 0.00 ONH HHH
I I OOH OHH
0.00 0.00 OO OO
0.0NH 0.00 OO OOH
0.00 O.NO ONH OOH
0.00 0.00 OOH OOH
0.0N N.ON OOH OO
N.OO 0.00 NHH OOH
0.00 N.OO OO ONH
0.00 0.00 OOH Om
O.NH 0.00 OOH OOH
O.HO N.OO ONH ONH
0.00 0.00 NOH ONH
0.00 O.NO OOH OO
>Um >mm fimm mm
N209004>Bm0m
000000000 00 00 I 0

OHH

OHH
NHH
OOH
OOH
OHH
OOH
OOH
ONH
NO

OOH

OHO

OO
OO

m0

OON

:mmz

OHNM
r—II-II—II—i

Hvamkol‘mCN

O Ooa

133

H0.0

O0.0
H0.0
O0.0
O0.0
O0.0
O0.0
N0.0
O0.0
H0.0
O0.0
OH.O
H0.0

mm

ONH

ONH
OOH
OOH
HOH
OOH
ONH
OOH
NOH
OOH
OO

OHH
OOH
ONH

OOH

OOH
HOH
OOH
OON
OOH
OOH
NOH
NOH
OOH
OOH
OOH
OOH

mm

4.50 0.04 040
I I 040
0.05 0.44 000
0.000 0.00 00
0.00 0.00 040
0.00 0.04 000
0.00 4.00 000
4.00 0.00 500
4.00 0.00 500
0.00 0.04 000
0.00 0.04 050
0.00 0.04 000
0.04 0.00 000
0.05 0.04 050
>o0 >00 000
0200000>0000
00o 000 I 0o 000

OHH

HOH
OOH
OOH
OOH
OO

OOH
OOH
ONH
OO

OOH
ONH
HOH
OO

NHH

HOH
OHH
OOH
OOH
OOH
OHH
OOH
OHH
OO

OOH
OHH
HO

OO

m0

ON.O

ON.O
ON.O
ON.O
ON.O
ON.O
O0.0
HN.O
ON.O
ON.O
O0.0

mm

OHH

OHH
NOH
HO

OHH
ONH
OOH
ONH
OHH
ONH
OO

OO

OHH
OOH

mZHHmmom

OOH

NOH
OOH
NOH
OON
OOH
OOH
OOH
OOH
OOH
OOH
OOH
OOH

mm

0.00 O.NO ONH OOH
I I OHH OHH
0.00 0.00 OO OO
0.0NH O.NO OO OOH
O.NO 0.0N OOH ONH
0.00 0.00 OOH OO
N.HN 0.0N OOH NO
N.OO 0.00 OHH OOH
0.00 0.00 OO OOH
0.00 0.00 OHH NO
O.NH N.OO OOH OOH
N.HO 0.00 ONH OHH
N.OO 0.00 OOH NHH
0.00 0.00 ONH OO
>Um >mm flmm mm
OZOBOO<>BmOm
HHOHUCOOO 00 OO I N

O

OHH

OOH
NHH
OOH
OOH
OOH
ONH
OOH
NNH
OO

NOH
OHH
OO

OO

OU

OON

C002

OI—INM
I-II—lI—Ir-l

r—INMQ‘LDKDNG'JG

O OOQ

134

OH

ON
OH
OH
HH
OH

Coffin—Om

rd

OOMI—iO

p

rH

mm.o OH mmH
mm.m OH NOH
oo.O mm mmH
Om.m OH OOH
mm.m mH mmH
oo.O mH mmH

mm mom mm

Ozoaooa>mmm
moo mom I No we

 

OO

OO
OO
OO
OOH
OHH

OOH

OO

ONH
OOH
OOH
OOH

OHH O.H O.

OO

ONH
OOH
OHH
OHH

OOMNN

It!

mu

COMP-lo

4.)

O0.0

N0.0
O0.0
NN.O
H0.0
N0.0

mm

AnamEOmm HmmHHV

MZHBmMBZH

HHH OOH mO omH
OOH Oom mO mm
ONH owH mm mHH
mOH NOH mw mmH
MOH mmH Om OHH
I OOH mOH MHH
mom mm <2m mm
OzoeomO>mmm
Houucoov moo wwm I m

NNH

OO

ONH
OOH
OHH
ONH

mu

OON

:mwz

HNMV‘Lfi

O O00

135

OH

ON
OH
OH
HH
OH
OH

OH
ON

«2

0.0 O.H
O O
O O
H O
O O
H O
H N
H H
H N
O O
m u

OOOO

O0.0
O0.0
O0.0
O0.0
O0.0
H0.0
O0.0
O0.0
O0.0

mm

N

OH OOH OOH
OH OOH OO
Om OOH OOH
I OOH OHH
OH OOH OOH
OH OOH OOH
Om OON OOH
HO OOH OOH
OH OOH OOH
ON OOH OON
mom mm «2

O20O00O>Omom

oo OON I No OO

 

OOH

ONH
OOH
OOH
OHH
OOH
OOH
OOH
OOH
OOH

NHH 0.0 0.0
OO

OOH
HOH
OO

OHH
ONH
ONH
OHH
OOH

OOOHONHNN
OOOOONI—{OO

(U
4.)

mu

Aucmemmm HmmHHO
mzHOmmezH

O0,0

O0.0
O0.0
O0.0
O0.0
O0.0
OOOO
O0.0
O0.0
ON.O

mm

OOH OOH HHH OHH
OOH OOH HO OOH
OHH OOH OOH OOH
I OOH OOH OOH
OOH OOH OOH OO
OOH OOH OO OHH
OON OON OOH OOH
OON OOH OHH OHH
OHO OOH OOH OOH
OHH OOH OHH OOH
mom mm OEO mm
OzoeouO>Omom
AHouucooO moo OON I No

HHH

OO

OOH
OOH
OO

OHH
OOH
OHH
OHH
OOH

m0

OON

cam:

HNMV‘WKDBGDON

O moo

136

OH

ON
OH
OH
HH
OH
OH

OH
ON

0.0 0.0
O O
H H
H O
O H
H O
N H
O O
O O
O O
m u

N0.0

N0.0
N0.0
ON.O
O0.0
N0.0
O0.0
O0.0
O0.0
N0.0

mm

OH NOH OOH
HH OOH OOH
OH ONH OOH
I OOH OOH
OH OOH OOH
OH OOH OOH
OO OHO OOH
OH OOH OHH
OH OOH OOH
OH OOH OOH
mom mm 42m
O2090u<>emom
moo OO I 0 OO

OOH

OOH
NOH
OOH
OOH
ONH
OOH
OHH
OOH
OOH

OHH O.H H.H O0.0
OOH O O O0.0
OOH O O O0.0
OOH H m O0.0
OO H O O0.0
OHH H O O0.0
OHH H O O0.0
OOH O O O0.0
OHH O m O0.0
OOH H H ON.O
mum m 2 u Om

Augmeawm HmmHHV
OzHOOmOzH

HOH OOH ONH HHH
OHH NOH OO OO
OHH OOH OO OHH
I OOH OOH OOH
OOH OOH HOH OO
OOH OOH OOH OOH
OON OON OOH ONH
OON OOH OHH OOH
OHO OOH OOH OOH
OHH OOH OOH OOH
mom mm 42m mm
Ozoeowa>emom
“Houucoov moo OON I O

O

NHH

NOH
ONH
OOH
OO

OHH
OHH
OOH
OHH
OOH

mu

OON

cmmz

r-‘INMVLDLOBCDON

O O00

137

OH

ON
OH
OH
HH
OH
OH

OH
ON

O.H 0.0

NMHHHNI—‘IOM

(U

NHOOONr—IOM

 

MOH NOH OOH
OOH OON OO
OOH OOH OO
I OOH OOH
OOH OOH OOH
OOH OOH OON
I OON HOH
ONH OOH OOH
I OOH OOH
OOH NOH OOH
mom Om «Em
Osceow<>emom
moo OON I No OON

ONH

ONH
OOH
OOH
OO

OO

NOH
OHH
OOH
OOH

OOH O.H 0.0 O0.0

OOH N O NOOO
ONH H H H0.0
OOH N H OOOO
OO N N I
OO O O O0.0
ONH H O O0.0
OO O O O0.0
OO N O N0.0
OOH H H ON.O
mom m E u

AucmaOmO HmmHHO

MZHBmmBZH

OOH

NHH
NHH

HHH
OOH
ONN
OON
ONN
OHH

mm mom

AHOHUCOUV

OOH OHH HOH OOH
OOH OO OO OOH
OOH OO Om OOH
OOH OOH OOH OOH
HOH OOH OO OO
OOH OOH OO OO
OON OOH HOH OOH
OOH OOH OO OO
OOH OOH OO OO
OOH OOH OOH HOH
mm OSO Om mom

O20900O>Omom

Nou OON I No OON

:mwz

HNMV‘LDKDFCDG

O OOQ

138

OOH
OOH
OOH

NHH
NON

OOH

OOH
OOH

NON

N0.0

N0.0
H0.0
O0.0
O0.0

OH OOH OOH
O OHH OOH
ON NOH OOH
I ONH OOH
O OOH OOH

OEOOOOO>OOOO
Nou OON I No OO
OH OOH OHH
O ONH OOH
ON OOH ONH
NH NOH OOH
Nom mm 42mm

Ozoaow<>mmm
Now OON I No OO

OOH
OOH
OOH

ONH
OOH

NOH

ONH
OOH

OOH

OOH
OHH
OHH

OO
OHH

OHH

OHH
OHH

ONH

m0

O0.0

O0.0
H0.0
ON.O
O0.0

NO OOH NOH NOH
OOH OHH OO OHH
OO OOH OHH OHH
I ONH OHH OO
OO OOH OO OHH
Ozoeoom>emom
AHouucooO Noo OON I N
OOH NOH OOH ONH
OOH ONH OOH OHH.
OO OOH OOH OOH
ONH OOH OHH OOH
Nom mm Ozmm Om
Osceomm>mmm
AHouucoov Nou OON I N

AOHmuud OHkucmmmz HOHuwmsmv

MZHBmmBZH

OOH
OHH
OHH

OO
OHH

O OON

HNH

ONH
OHH

ONH

m0

0 OON

cmwz

r-INM'Q‘

cmmz

t-INMV‘

O O00

139

OOH

OOH
OOH
NHH
NON

OOH

OOH
OOH
NHH
NON

42m

O0.0
H0.0
O0.0
O0.0
O0.0

ON.O

HN.O
ON.O

O0.0

mm

Tux
j

HHH OOH ONH ONH

OOH OHH OHH ONH
OOH OOH OHH OOH
I NOH OOH OO
ONH OOH ONH OOH

VSOBOU<>EmOm

NOD OON I NO OON

NH NOH OHH OOH

O OHH ONH OOH
HN OOH OHH OOH

O NOH ONH OOH
Nom mm 42mm mm
Osceou<>emom

N N

00 OO I 0 mo

OOH
OHH
NHH

OO
OHH

OHH

OHH
OHH

OHH

m0

O0.0

O0.0
O0.0
O0.0
O0.0

O0.0
O0.0
H0.0
O0.0
O0.0

mm

OOH HOH OOH HOH
ONH OHH OO OOH
OOH OOH OOH OHH
I ONH OOH OO
OO OOH OO OHH
Osceoo<>amom
AHouucoov Noo OON I N
OO OOH HOH OHH
OOH OHH NO OOH
OO OOH OOH OHH
I ONH OOH OO
OOH NOH OOH OHH
Now an «ZOO mm
OsceowO>aOom
HHouuzoov Nou OON I N

Amumuu< OHHmucmmmS HOHHmmsmO

MZHBmMBZH

OOH
OHH
OHH
OO

OHH

O OON

OHH
OHH
ONH
OO

OHH

m0

0 «ON

C002

I—iqu‘

cmmz

HNMQ‘

O moo

140

OHH

OOH
OO

NHH
NOH
OO

OO

OOH
OOH
OOH
OOH

O0.0

OH.O
O0.0
O0.0
O0.0
O0.0
N0.0
O0.0
OH.O
O0.0
O0.0

mm

OH NOH ONH
OH NOH OOH
O OOH OON
OH OHH OO
HN OOH OO
HN NOH OHN
O OOH NO
ON OOH OO
OO NOH NO
OH NOH OO
NH OOH OOH
Nom mm mm
Osceowm>mmm
Nou OON I 0 OO

OOH

ONH
OOH
OOH
OOH
OOH
OHH
OOH
OOH
OOH
OHH

OHH

OO

OOH
OOH
OOH
OOH
OO

ONH
OOH
OOH
OO

m0

WMZOHM

O0.0

O0.0
H0.0
O0.0
O0.0
O0.0
N0.0
O0.0
O0.0
N0.0
O0.0

mm

HNH

NO

OOH
NHH
OHH
OOH
OOH
OHH
OOH
OOH
OO

mom

HHOHOCOUO

HOH OO ONH
NOH OO OO
NOH OO OOH
ONH OO OOH
OOH OO OOH
OOH OOH OHH
OOH OO OOH
OOH OO OOH
OON OO OOH
NOH OO OHH
OOH OO OO
mm O OO
Ozoaow¢>mmm
N N

on OON I

O

OHH

OO

OOH
NOH
OOH
OOH
OOH
HOH
OOH
OOH
NO

m0

OON

cmmz

r-i

I—INMV‘LOOFQQO

* O00

141

OOH

OOH
OO

NHH
NOH
OO

OO

OOH
OOH
OHH
OOH

O0.0

O0.0
O0.0
O0.0
O0.0
O0.0
O0.0
O0.0
HH.O
H0.0
O0.0

mm

 

OH OOH OOH
OH OOH OOH
O OOH OHN
OH OHH OOH
OH OOH OO
ON OOH OOH
O OOH OO
OO OOH OON
OO NOH OON
HH OOH OO
HH ONH OOH
N

om mm mm

Ozoeoo¢>emom

Nou OON I No OO

OOH

OOH
HOH
OON
NOH
OO

ONH
OOH
OHH
ONH
OO

OOH

OO

ONH
HOH
OHH
HO

OOH
OOH
OOH
OHH
OO

m0

OMZQHM

O0.0

O0.0
H0.0
N0.0
OOoO
H0.0
O0.0
O0.0
H0.0
N0.0
O0.0

mm

NHH NOH HO NOH
NO NOH OO OO
OHH ONH OOH ONH
OOH OOH 0O mmH
OO NOH OO. ONH
ONH OOH NHH OO
OOH HNH OO OO
OHH OOH OOH HOH
ONH OOH Om mm
OOH OOH OO OHH
OO OmH MO OO
Nom mm mm mm
Osceow<>emom
AHouucooO Nou OON I N

O

OOH

OO
OOH
OOH
OHH
OO
OO
NOH
OO
OHH
OO

mu

OI

OON

ammz

I—i

HNMQ‘LGKDNwONO

# O00

142

OOH

OOH
OO
NHH
NOH
OO
OO
OOH
OOH
OHH
OO

ON.O

HOoO
O0.0
ON.O
ON.O
ON.O
NN.O
OH.O
ON.O
ON.O
ON.O

mm

OH
OH
OH
OH

ON
OO

NOm

 

HOH OOH ONH
OOH NO OOH
OOH OOH OOH
OOH OOH OHH
OOH OO ONH
OOH ONH OO
OOH OOH ONH
OOH OOH ONH
OON OON ONH
OOH OO OHH
ONH OO OO

mm mm m

Osceoo<>emom

Nou OO I No OO

 

OOH

OO

OOH
OHH
NOH
OO

OOH
OHH
OOH
OHH
OO

m0

MMZQHK

O0.0

N0.0
O0.0
H0.0
O0.0
H0.0
N0.0
O0.0
H0.0
O0.0
O0.0

mm

OHH

OO

OHH
OHH
OOH
OOH
OHH
OHH
ONH
OOH
OOH

NonH

HHouucoov

OOH OO HOH
NOH OO OO
ONH OOH OOH
OOH HO OOH
OOH OO ONH
OOH OO OO
HNH OOH OOH
OOH OO OOH
NOH OO OOH
OOH OO OHH
ONH OO OO
mm mm mm
Osceoom>emom
Nou OON I N

O

OOH

OO

ONH
HHH
OOH
OO

OOH
OHH
OOH
OOH
OO

m0

OON

cams

I-i

HNMVmKOFm¢O

O OOQ

143

OOH

OOH
OO
NHH
NOH
OO
OO
OOH
OOH
OHH
OO

FDA”

ONH OOH ONH NNH
OO HOH OO OO
OOH OOH OOH OOH
ONH NHH OOH OOH
ONH OOH OOH OOH
OOH NOH OOH OOH
OHH HNH OOH ONH
OHH OOH OOH OOH
OOH NOH ONN OO
ONH OOH OO OOH
ONH ONH HO OO
Nom mm mm mm
OsceowO>emom
Noo OON o OON

OOH

OO
ONH
OHH
OOH
OO
OOH
OOH
OO
OHH
OO

m0

NWZDHM

O0.0

O0.0
O0.0
O0.0
H0.0
N0.0
H0.0
N0.0
O0.0
O0.0
O0.0

mm

ONH OOH OO OO
OO OOH OO OO
ONH HOH OO ONH
OOH NHH OO OHH
OOH OOH OO OOH
OOH OOH OO OOH
OOH HNH OO OO
OHH OOH OHH OOH
NOH OON NOH OO
NOH OOH OO OOH
OOH ONH HO OO
Nom mm O OO
Ozoaow<>emom
AHouuaooO Ooo OON I N

O

HOH

OO
ONH
OHH
OOH
OOH
OO
OOH
OO
OOH
OO

m0

OON

com:

r-l

HNMQ‘mwl‘me

* Ooa

144

 

 

OOH OO HO OON OO OOH OOH OOH ONH OO OO OOH NOH cam:
OOH OO OO OOH OO OO HO OO OO OO OO NO OO O
OO OO OO OOH OOH OHH OHH OO OOH OO OO ONH OHH O
OOH OO OHH OON OO OOH OOH OHH OOH OO OO OOH OOH O
OO OO OO OON HNH OO OO ONH OO OO OOH OO OO O
OOH HO OO OON OO OOH OOH OOH OOH OO OO OOH OOH m
OHH OO NO OON HO OOH OHH OO OOH OO OO OOH OHH H
Osceoo<>emom
ONH OO OOH OON OO ONH ONH OOH OOH OO OO ONH OOH cam:
ONH OO OOH OON OO OOH OOH OOH OOH OO OOH OOH OOH O
OHH OO OHH OON OO OOH OOH OO OOH OO OO OOH OOH O
NOH HO OOH OOH OO OOH OOH HO HOH OO OO OOH ONH O
OO OO NOH OHN NHH ONH HNH OOH OOH OO OOH OHH OOH O
OOH OO OHH OON OO OOH HOH OO OOH OO OO HOH OOH m
OOH OO OO OON OO OOH OOH HO OHH OO OO OOH OOH H
mm mm mm mum mm mm mum mm OAH mum mm mm mom O moo
mmo OOHO Houucou mmu 304 Houucou
OEOOQUO>OOO

NMZQHM

Dog #

OkDCDQChU‘bU-JNH

H

Mean

OKOCDQGUIJ-EnWNH

H

Mean

OkOWflO‘UIJ-XLAJNH

H

Mean

102
101
103
130
100
104
100

96

81
115

103

155
106
115
141

95
133

97
120
100
125

119

24
17
17
23
17
18
31
25
31
18

22

30"

100
103
102
132
100
104
103

96

83
115

104

157
105
117
141

96
135

99
120
100
125

120

145

CORONARY VASCULATURE--STUDY 1

0%

O
2

- 20% CO
2

(PREVAGOTOMY)

SYSTEMIC ARTERIAL PRESSURE

60"

100
105
111
138
100
108
110

96

85
117

108

CORONARY ARTERY PRESSURE

158
107
121
143
100
135

99
119
100
125

121

90"

107
113
130
146
109
107
115
104

90
120

114

164
108
122
144
103
138

98
118
100
120

122

120"

110
112
132
152
115
108
120
105

96
126

118

165
109
125
142
108
140

95
117
100
112

121

150"

112
114
134
155
115
107
120
105

98
127

119

163
111
128
140
111
140

97
116
102

93

120

LEFT VENTRICULAR CONTRACTILE

24
17
17
23
17
18
31
25
31
18

22

23
17
17
23
17
18
31
25
31
17

22

22
15
17
21
17
17
30
24
30
16

21

22
15
16
2O
16
17
30
24
29
15

20

22
15
16
20
16
17
29
24
29
14

20

180"

115
117
128
150
113
105
120
104
100
127

118

167
113
128
140
112
140

95
115
117

90

122
FORCE

22
15
16
20
16
17
29
23
3O
13

20

210"

117
108
128
150
113
105
120
105
100
125

117

170
113
127
138
115
141

93
115
119

88

122

22
15
16
20
16
17
28
‘23
3O
12

20

 

Tut-=1 ":1 .

Dog #

OkomQONUIbWNI-J

H

Mean

OKDCDQmm-bwwld

H

Mean

OOCDQO‘U‘IanNH

H

Mean

C

80
107
90
113
84
110
75
105
63
108

94

148
164
137
135

158

85
113
140
160

133

17
24
18
21
24
21
15
25
26
21

21

30"

80
110
93
110
84
109
75
105
62
105

93

149
166
138
136

93
159

85
114
140
160

134

146

CORONARY VASCULATURE--STUDY 1

0% O2

SYSTEMIC ARTERIAL PRESSURE

60"

82
120
100
110

90
110

90
105

75
105

99

CORONARY ARTERY PRESSURE

150
167
139
135

95
158

91
116
143
162

136

90"

83
131
126
123
100
110

90
110
125
117

112

152
170
140
140

95
162

90
118
115
158

134

120"

90
140
150
138
105
105

97
125
135
125

121

155
175
143
139

95
155

93
117

90
150

131

150"

92
143
165
165
101
102
100
124
140
138

127

156
178
146
139

95
161

95
120

90
113

129

LEFT VENTRICULAR CONTRACTILE

17
23
18
21
24
21
15
25
26
21

21

17
22
18
21
24
21
15
25
26
21

21

16
20
15
20
24
20
14
24
23
19

20

16
18
14
19
24
19
13
19
20
18

18

15
18
13
18
24
20
12
18
18
14

17

- 20% C02(POSTVAGOTOMY)

180"

102
146
175
195
103
100
101
126
143
140

133

157
185
150
140
100
162

92
117

85

80

127
FORCE

15
17
12
18
24
20
12
18
18
11

17

210"

118
146
195
215
105

95
131
140
140

156
186
140
140
97
160
115
85
82

129

1
J.

17

1
.L

16
24
2O

17
18
ll

17

 

I"

U
0
c5mnn~4mcnnuynaw O

H

Mean

OkomflmmwaI-J

H

Mean

OWGQtfiLflbWNH

H

Mean

95
105
110
112

45

75

70
101

78
100

89

153
155
135
133
114
135

70
130

75
150

125

17
29
16
21
20
19
18
27
28
19

21

30"

92
106
106
115

47

75

70
103

80
100

89

152
157
135
135
115
136

71
130

75
150

126

147

CORONARY VASCULATURE--STUDY l

0% 02

SYSTEMIC ARTERIAL PRESSURE

60"

86
101
110
120

50

74

73
101
105
100

92

CORONARY ARTERY PRESSURE

155
156
136
135
115
138

75
130

75
154

127

- 5% COZ(POSTVAGOTOMY)

90"

93
110
134
133

55

75

85
108
115
100

101

157
160
135
136
115
140

75
130

65
153

127

120"

93
122
157
140

68

77

90
112
115
105

108

159
164
136
136
115
136

74
130

55
151

126

150"

92
128
162
146

70

80

92
116
115
106

111

160
164
141
133
116
137

74
128

50
150

125

LEFT VENTRICULAR CONTRACTILE

16
29
15
21
20
19
18
27
28
19

21

15
28
13
21
20
19
17
27
28
19

21

15
27
13
20
20
19
16
26
19
19

19

15
24
13
20
20
19
16
25
15
19

18

15
23
11
19
20
19
16
23
14
19

18

180"

92
130
165
155

75

80

95
124
115
109

114

158
166
146
137
114
136

75
127

50
145

125
FORCE

14
22
11
19
20
l9
16
25
14
18

18

210"

133
165
175
75
82
93
123
115
113

117

157
170
148
133
113
135

74
126

50
143

125

14
21
11
19
20
19
16
25
14
17

18

 

148

CORONARY VASCULATURE--STUDY l

20% O2 - 20% COZ(POSTVAGOTOMY)

SYSTEMIC ARTERIAL PRESSURE

 

Dog # C 30" 60" 90" 120" 150" 180" 210"
l 100 98 101 104 108 108 110 116
2 _ _ - _ - _ _ -
3 110 110 115 138 141 146 148 142
4 110 110 110 118 122 123 130 133
5 81 80 87 95 98 101 101 99
6 70 70 75 80 80 80 78 78
7 102 99 110 110 105 105 105 105
8 102 105 104 106 108 106 107 105
9 68 68 97 100 103 102 107 107

10 105 105 106 115 118 120 120 120

Mean 94 94 101 107 109 110 112 112

CORONARY ARTERY PRESSURE

1 164 162 165 168 170 168 165 165

2 _ _ _ - - - _ _
3 148 147 147 146 148 146 146 144
4 142 142 14] 146 143 143 137 137
5 100 99 100 98 97 96 95 93
6 150 151 154 153 154 155 154 155
7 82 80 81 .80 78 80 77 77
8 132 132 132 133 135 132 134 134
9 133 136 139 135 137 135 135 135
10 135 140 142 142 140 137 138 139
Mean 132 132 134 133 134 132 131 131

LEFT VENTRICULAR CONTRACTILE FORCE

1 22 22 21 21 20 20 19 1
2 ... _ _. _ _ .. _. .-
3 16 16 16 15 14 14 14 14
4 22 22 22 21 20 20 2O 19
5 23 23 23 23 22 22 22 22
6 24 24 24 23 23 23 22 22
7 18 18 17 17 17 16 16 16
8 28 28 27 27 26 26 26 26
9 27 27 27 26 26 25 25 25
10 20 20 20 18 17 17 16 16

Mean 22 22 22 21 21 20 20 20

149

CORONARY VASCULATURE--STUDY 2

0% O2 ‘ 20% CO2 (PREVAGOTOMY)

SYSTEMIC ARTERIAL PRESSURE

Dog # c 30" 60" 90" 120" 150" 180" 210" 240"
1 96 97 99 105‘ '107 113 116 118 125
2 105 105 '105 106 106 107 108 108 109
3 120 120 140 138 143 145 150 150 150
4 136 140 150 162 167 165 170 168 167
5 95 95 96 97 104 108 112 115 118
6 116 120 125 134 134 134 133 133 133

Mean 111 113 119 124 127 129 132 132 134

CORONARY ARTERY PRESSURE

 

150 150 150 152 153 153 150 151 155
128 129 130 131 131 129 128 127 126
125 125 130 120 132 140 145 148 148
125 126 125 132 135 140 139 139 137
138 138 138 137 135 130 128 127 125

81 83 84 84 85 87 88 93 97

mmanH

Mean 125 125 126 126 129 130 130 131 131

LEFT VENTRICULAR CONTRACTILE FORCE

1 43 42 43 41 39 38 37 37 36
2 24 24 24 22 20 19 19 18 18
3 14 14 14 13 13 12 12 13 13
4 37 37 37 33 31 31 30 30 30
5 32 32 32 32 31 29 29 29 29
6 35 34 3O 26 26 27 27 27 27

Mean 31 31 3O 28 27 26 26 26 26

Dog #

mmwat—I

Mean

ONUIubUJNl-J

Mean

mmprt—I

Mean

C

67
91
62
133
80
105

90

131
144

86
140
130
170

134

44
25
36
41
35
40

37

30"

67
91
64
134
80
105

90

130
144

86
140
132
170

134

150

CORONARY VASCULATURE--STUDY 2

O
0% 2

SYSTEMIC ARTERIAL PRESSURE

60"

70
90
70
157
85
122

99

CORONARY ARTERY PRESSURE

131
146

86
140
135
170

135

- 20% COZ(POSTVAGOTOMY)

90"

90
91
125
182
115
140

124

132
150

88
134
127
170

134

120"

118

95
160
192
125
168

143

115
150

90
134
119
145

126

150"

133

96
175
195
133
180

152

108
149

95
134
120
145

125

LEFT VENTRICULAR CONTRACTILE

44
25
36
41
35
38

37

44
25
34
35
35
37

35

45
24
30
32
30
31

32

41
21
25
28
25

28

36
20
22
28
27

27

180"

128

96
178
205
135
192

156

115
149

98
140
123
158

131

FORCE

35
20
26
28
27

27

210"

126
100
178
203
131
205

157

125
148
100
146
125
158

134

37
19
26
28
27

27

240"

127

98
175
200
132
205

156

125
148
101
152
123
160

135

37
20
27
28
27

28

 

Dog #

Mean

Mean

NH

Mean

C

132
100

116

120
150

135

37
33

35

30"

130
100

115

120
150

135

151

CORONARY VASCULATURE--STUDY 2

5% o - 2+3 co

2 (POSTVAGOTOMY)

2

SYSTEMIC ARTERIAL PRESSURE
60" 90" 120" 150"

132 135 137 130
102 103 105 101

117 119 121 116

CORONARY ARTERY PRESSURE

118 116 115 114
154 154 153 154

136 135 134 134

180"

135
100

118

115
155

135

LEFT VENTRICULAR CONTRACTILE FORCE

37
33

35

37 37 37 37
33 33 33 33
35 35 35 35

36
33

35

210"

135
100

118

113
155

134

35
33

34

240"

135
103

119

114
155

135

36
33

35

 

152

CORONARY VASCULATURE--STUDY 2

10% 02 - 24% C02(POSTVAGOTOMY)

SYSTEMIC ARTERIAL PRESSURE

Dog # C 30" 60" 90" 120" 150" 180" 210" 240"
1 77 77 78 80 80 82 81 80 83
2 98 98 97 95 96 95 95 95 95
3 62 60 56 55 59 56 56 54 53
Mean 79 78 77 77 78 78 77 76 77

CORONARY ARTERY PRESSURE

 

1 123 123 124 124 125 125 125 126 126
2 143 143 143 144 143 143 143 142 142
3 80 79 76 75 74 72 71 70 70

Mean 115 115 115 114 114 113 113 113 113

LEFT VENTRICULAR CONTRACTILE FORCE

1 37 37 37 37 37 37 37 37 37
2 24 24 24 24 24 24 24 24 24
3 33 33 33 33 33 33 33 33 33

Mean 47 47 47 47 47 47 47 47 47

153

CORONARY VASCULATURE--STUDY 2

20% O2 - 10% C02(POSTVAGOTOMY)

SYSTEMIC ARTERIAL PRESSURE

Dog # C 30" 60" 90" 120" 150" 180" 210" 240"
1 75 75 77 80 80 80 80 78 78
2 95 96 97 98 100 98 99 99 99
3 66 65 72 82 90 94 96 96 95
4 125 125 125 135 136 140 140 140 140
5 95 96 99 100 101 100 100 100 98
6 105 105 105 110 114 114 113 115 115

Mean 94 94 96 101 104 104 105 105 104

 

CORONARY ARTERY PRESSURE

1 127 127 127 128 127 126 127 126 125
2 139 139 139 140 140 141 142 141 140
3 90 90 95 93 91 90 92 91 93
4 120 120 123 124 123 122 122 122 123
5 122 123 126 125 125 124 125 125 125
6 157 157 157 159 156 156 157 159 158
Mean 126 126 128 128 127 127 128 127 127
LEFT VENTRICULAR CONTRACTILE FORCE
1 40 40 40 40 39 39 29 39 39
2 23 23 23 22 22 22 22 22 22
3 37 37 37 37 37 37 37 37 37
4 40 40 40 40 40 38 39 38 38
5 31 31 32 31 30 30 31 30 30
6 42 42 42 41 37 38 40 39 40

Mean 36 36 36 35 34 34 35 34 34

154

CORONARY VASCULATURE--STUDY 2

10% O2 - 10% COZ(POSTVAGOTOMY)

SYSTEMIC ARTERIAL PRESSURE

Dog # C 30" 60" 90" 120" 150" 180" 210" 240"
1 67 68 69 76 80 83 84 85 87
2 92 91 92 95 95 94 93 94 94
3 68 70 67 86 92 95 103 105 103
4 125 125 127 133 137 146 150 156 156
5 87 87 87 87 90 92 92 93 93
6 105 105 106 115 114 115 116 115 115
Mean 91 91 91 98 101 104 106 108 108

 

CORONARY ARTERY PRESSURE

1 128 129 129 129 128 127 128 128 128
2 141 142 142 143 145 145 134 145 145
3 96 95 93 94 9O 87 89 88 87
4 123 124 125 124 122 120 118 117 117
5 125 126 125 125 126 127 128 127 125
6 165 164 165 164 164 164 162 163 163
Mean 130 130 130 130 129 128 128 128 128
LEFT VENTRICULAR CONTRACTILE FORCE
l 40 40 4O 40 39 39 39 40 38
2 28 28 28 26 26 26 25 26 2
3 38 38 37 37 36 34 35 36 37
4 41 40 40 40 40 39 38 27 27
5 33 33 33 32 32 32 32 32 31
6 42 42 42 38 38 39 39 39 40

Mean 37 37 37 36 35 35 35 35 35

APPENDIX B

STATISTICAL METHODS

155

 

._.. m

156

STATISTICAL METHODS

Since in every dog a control period preceded each
experimental maneuver, each animal served as its own control.

To statistically analyze the data the Student's t test for

paired observations was used. This approach was used in Emm‘
order to eliminate the source of extraneous variance exist-

ing from pair to pair. This was done by calculating the

variance of the differences rather than that among the 'j

 

individuals within each sample. ——
The parameters analyzed by this statistical method

included the systemic arterial pressure, organ perfusion

pressure, blood flow, heart rate and left ventricular contrac-

tile force data. The animal's control data for each of the

above parameters were used as one of the paired values while

the data obtained during the experimental maneuver were used

 

as the other value. The mean for the controls was designated
£1 and the mean for the experimentals designated £2. The
mean difference between the values was £1 - £2 which also
equaled d. 35 equaled the standard error of the mean paired
difference and was calculated from
A 2 D? - ( 2 D, )2/n
s: 13 :3

 

n (n - 1)

157

The test statistic (t) . The hypothesis being tested

was

If the sample t was greater than the tabulated value with

 

which it was compared, then the null hypothesis was rejected ”If
and the alternative accepted. For this study a significance
level of .05 was used.
In the case of the comparison of the percent changes in
vascular resistance (Table 9), the t test modified for un- raj

paired observations and unequal variances was used. A suffi-
ciently accurate approximation for determining a significant

value of t' was calculated from

wl tl + w2 t 2

 

2 _ 2
where wl - sl/nl, w2 — 52/n2' and t1

of Student's t for nl - l and n2 - 1 degrees of freedom at

and t2 are the values

the .05 significance level. This approximation erred slightly
on the conservative side in that the value of t' required

for significance may have been slightly too large.

 
    

”7111111111th7!flifllilEfl'l‘fllfll’lfllWlflmS

1293 0