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Reflex control of ACTH, cortisol, AVP, and renin responses to slow hemorrhage in fetal sheep

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Reflex control of ACTH, cortisol, AVP, and renin responses to slow hemorrhage in fetal sheep
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Chen, Hong-Gen
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English
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xii, 113 leaves : ill. ; 29 cm.

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Subjects / Keywords:
Blood ( jstor )
Chemoreceptors ( jstor )
Fetus ( jstor )
Hemorrhage ( jstor )
Hormones ( jstor )
Hypercapnia ( jstor )
Lambs ( jstor )
Plasmas ( jstor )
Secretion ( jstor )
Sheep ( jstor )
Argipressin -- pharmacology ( mesh )
Corticotropin -- pharmacology ( mesh )
Hemorrhage ( mesh )
Hydrocortisone -- pharmacology ( mesh )
Renin -- pharmacology ( mesh )
Sheep -- physiology ( mesh )
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bibliography ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1991.
Bibliography:
Includes bibliographical references (leaves 97-112).
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Hong-Gen Chen.

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University of Florida
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University of Florida
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Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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ocm25487736
001664825 ( ALEPH )

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REFLEX CONTROL OF ACTH, CORTISOL, AVP, AND RENIN
RESPONSES TO SLOW HEMORRHAGE IN FETAL SHEEP


















By

HONG-GEN CHEN


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


1991




REFLEX CONTROL OF ACTH, CORTISOL, AVP, AND RENIN
RESPONSES TO SLOW HEMORRHAGE IN FETAL SHEEP
By
HONG-GEN CHEN
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1991


To my parents Qinshan Chen and Xiuying He, and to my husband Ke Wu.


ACKNOWLEDGEMENTS
I wish to express my gratitude and appreciation to Dr. Charles E. Wood, chairman of
my supervisory committee, for his patience, guidance, and encouragement throughout the
fulfillment of this work. He has not only provided an invaluable academic direction in the
research but also set an example of responsibility and dedication.
My sincere thanks are extended to the members of my committee, Drs. Robert M.
Abrams, Willa H. Drummond, Maureen Keller-Wood, and Wendell N. Stainsby. In particular,
I wish to thank Dr. Maureen Keller-Wood for her very helpful suggestions and criticism for
the project and Dr. Willa H. Drummond for introducing me to this program and her continued
encouragement and advice. Special thanks must be also extended to Mr. Curt Kane and Mrs.
Ellen Manlove, and also, to Miss. Christine Taranovich, Miss. Jennifer Johnson, and Dr.
Timothy Cudd for their friendship and expert technical assistance in running hormone assays
or doing surgeries and experiments. Gratefulness also goes to the faculty members and my
fellow students in the Department of Physiology for their concern, advice and support.
Last but not least, I am greatly indebted to my husband, Ke Wu, and my parents for
their love, backing, and understanding. My gratitude to them is beyond description.
in


TABLE OF CONTENTS
ACKNOWLEDGEMENTS iii
LIST OF TABLES vi
LIST OF FIGURES vii
KEY TO ABBREVIATIONS ix
ABSTRACT xi
CHAPTER 1 INTRODUCTION 1
CHAPTER 2 BACKGROUND REVIEW 3
2.1 A Brief Review of the Fetal Circulatory System 3
2.2 The Development of Autonomic Control of the Heart 4
2.3 The Development of Baroreflex Control of Circulation in Fetuses 6
2.4 The Development of Chemoreflex Control of Circulation in Fetuses 8
2.5 The Fetal ACTH, Cortisol, AVP and Renin Responses 11
2.5.1 ACTH and Cortisol 11
2.5.2 AVP 16
2.5.3 Renin 18
2.6 Summary 19
CHAPTER 3 GENERAL METHODOLOGY 21
3.1 Surgical Procedures of Catheterization and Denervation 21
3.2 General Preparation for Experiments and Hemodynamic Data
Collection 22
3.3 Handling and Analysis of Blood Samples 23
3.4 Calculations and Statistical Analyses 25
CHAPTER 4 THE ROLE OF VAGOSYMPATHETIC AFFERENT FIBERS
IN THE CONTROL OF ACTH, VASOPRESSIN, AND RENIN RESPONSES
TO HEMORRHAGE IN FETAL SHEEP 26
4.1 Introduction 26
4.2 Materials and Methods 27
4.3 Results 27
4.4 Discussion 39
IV


CHAPTER 5 ACTH, AVP, AND RENIN RESPONSE TO INTRAVENOUS
INFUSION OF HYDROCHLORIC ACID ARE CHEMORECEPTORS
RESPONSIBLE FOR FETAL HORMONE SECRETION? 44
5.1 Introduction 44
5.2 Methods 45
5.3 Results 46
5.4 Discussion 53
CHAPTER 6 REFLEX CONTROL OF FETAL ARTERIAL PRESSURE
AND HORMONAL RESPONSES TO SLOW HEMORRHAGE 58
6.1 Introduction 58
6.2 Methods 58
6.2.1 Experimental Protocol 59
6.2.2 Calculated Variables 60
6.3 Results 62
6.3.1 Changes in Hemodynamic Variables During Hemorrhage 62
6.3.2 Changes in Blood Gases During Hemorrhage 62
6.3.3 Changes in Plasma Hormone Levels 64
6.3.4 Blood Volume Restitution 64
6.4 Discussion 67
6.4.1 Alterations in Blood Gases and Vascular Pressures 72
6.4.2 Reflex Hormonal Responses 74
6.4.3 Defense of Blood Volume 75
CHAPTER 7 THE ACTH AND AVP RESPONSES TO NORMOXIC
HYPERCAPNIA IN FETAL AND MATERNAL SHEEP 77
7.1 Introduction 77
7.2 Methods 78
7.3 Results 79
7.3.1 Responses in Fetuses 79
7.3.2 Responses in Ewes 81
7.4 Discussion 88
CHAPTER 8 SUMMARY 91
REFERENCES 97
BIOGRAPHICAL SKETCH 113
v


LIST OF TABLES
Table 4-1. Values of correlation coefficients relating fetal plasma hormone
concentrations to pHa, MAP, and CVP 35
Table 5-1. Results of ANOVAs 48
Table 5-2. Fetal plasma cortisol concentrations 51
Table 5-3. Fetal hematocrit 54
Table 6-1. Initial and final fetal blood volume and fetal blood volume
restitution 69
Table 7-1. Fetal Means & SEs of HCT, plasma potassium & sodium 82
Table 7-2. Maternal means & SEs of HCT, plasma potassium & sodium 87
vi


LIST OF FIGURES
Figure 4-1. Fetal MAP and HR during hemorrhage 28
Figure 4-2. Fetal CVP during hemorrhage 30
Figure 4-3. Fetal PaQ2, PaCG2, and pHa during hemorrhage 31
Figure 4-4. Fetal Hct during hemorrhage 32
Figure 4-5. Fetal Plasma ACTH and cortisol concentrations during hemorrhage. . 33
Figure 4-6. Fetal Plasma AVP concentration and PRA during hemorrhage 34
Figure 4-7. Relations among pHa and fetal plasma ACTH, AVP and PRA 37
Figure 4-8. Distribution of r values of fetal pHa, MAP, and CVP vs
Lg ACTH, AVP, or PRA 38
Figure 5-1. Fetal pHa, PaC02, and Pa02 during intravenous infusion of HC1 47
Figure 5-2. Fetal MAP and HR during intravenous infusion of HC1 49
Figure 5-3. Fetal plasma ACTH, AVP, and PRA during intravenous
infusion of HC1 50
Figure 5-4. Relationships between arterial H+ concentration, PaC02 and plasma ACTH,
AVP, and HR in 0.50 meq/min group 52
Figure 6-1. Fetal MAP, HR and CVP during hemorrhage 63
Figure 6-2. Fetal PaQ2, pHa and PaC02 during hemorrhage 65
Figure 6-3. Fetal plasma ACTH, cortisol, AVP and PRA during hemorrhage 66
Figure 6-4. Fetal volume restitution 68
Figure 6-5. Fetal Hct, plasma protein, potassium and sodium 70
Figure 6-6. Percent changes in fetal plasma protein concentration 71
Figure 7-1. Fetal pHa, PaCQ2, and PaG2 in normocapnia and hypercapnia studies. 80
Figure 7-2. MAP, CVP and HR in normocapnia and hypercapnia studies 83
vii


Figure 7-3. Fetal plasma ACTH and cortisol concentration in
normocapnia and hypercapnia 84
Figure 7-4. Fetal plasma AVP concentration in normocapnia and hypercapnia
studies 85
Figure 7-5. Maternal pHa, PaC02 and Pa02 in normocapnia and hypercapnia
experiments 86
Figure 7-6. Maternal plasma ACTH, cortisol and AYP concentration in
normocapnia and hypercapnia studies 89
viii


KEY TO ABBREVIATIONS
ACTH
adrenal corticotropic hormone
ANOVA
analysis of variance
AVP
arginine vasopressin
BV0
initial blood volume
BVt
subsequent blood volume at each time point
CVP
central venous pressure
EDTA
ethylenediaminetetraacetic acid
FBS
fetal bovine serum
FRCV
the fractional red cell mass
Hct
hematocrit
Hct0
initial hematocrits
Hctt
subsequent Hct at each time point
HR
heart rate
MAP
mean arterial pressure
Po
the plasma protein concentration before hemorrhage
%APa
actual % changes of plasma protein concentration
PaC02
arterial PC02
Pa02
arterial PQ2
%APC
theoretical %changes plasma protein concentration
Pc
plasma protein concentration
PHa
arterial pH
POMC
proopiomelanocortin
IX


PRA
Prf
Pt
PVN
RBC0
RBCt
%R
RIA
SEM
SON
vr
plasma renin activity
the protein concentration in restitution fluid
the protein concentration at each time point
paraventricular nucleus
initial red blood cell mass
subsequent red blood cell mass at each time point
percent changes of the blood volume restitution
the blood volume restitution during hemorrhage
radioimmunoassay
standard error of the mean
supraoptic nucleus
the blood volume removed during hemorrhage
x


Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
REFLEX CONTROL OF ACTH, CORTISOL, AVP, AND RENIN
RESPONSES TO SLOW HEMORRHAGE IN FETAL SHEEP
By
Hong-gen Chen
May 1991
Chairman: Charles E. Wood
Major Department: Physiology
To investigate the afferent pathway for controlling fetal ACTH, AVP and PRA
responses to slow hemorrhage, forty-six chronically catheterized late gestational fetal sheep
were studied.
Experiment I investigated the role of the vagus nerve. One hundred and forty-three
ml blood was withdrawn within two hours from five bilaterally vagotomized and six intact
fetuses. No significant differences in the stimulation of the hormones were found between
groups. The hormone stimulation was better correlated to the changes in pHa than in blood
pressures, suggesting that the responses in the fetus are possibly by chemoreceptors.
Experiment II tested the effect of chemoreceptors. HC1 was infused at three different
rates to fetuses. Infusions at the highest rate (0.50 meq/min) caused severe metabolic
acidemia and significantly stimulated plasma ACTH and AVP but not PRA. It is speculated
that the ACTH and AVP responses to acidemia are chemoreceptor mediated.
In Experiment III, 143 ml blood was withdrawn within two hours from twenty-six
fetuses, which were either intact or bilaterally carotid sinus denervated plus vagotomized, in
order to identify the peripheral chemoreceptors effect during hemorrhage. Denervated
xi


fetuses were studied with or without simultaneous infusion of phenylephrine. None of the
hormonal responses was attenuated by denervation, and phenylephrine infusion attenuated or
inhibited ACTH and AVP but not PRA when the exaggeration of MAP, pHa and PaC02 in
denervated fetuses was prevented. Thus the hormonal responses to slow hemorrhage was
concluded not being mediated by peripheral chemoreceptors.
Experiment IV quantified fetal plasma ACTH and AVP responses to hypercapnia and
tested the role of peripheral chemoreceptors. Six out of eleven fetuses were bilaterally carotid
sinus denervated and vagotomized. Each subject was studied under normocapnia control and
hypercapnia. Hypercapnia was induced by a C02 mixed-gas inhaled by the ewe. Hypercapnia
doubled fetal plasma AVP; denervation did not attenuate the response. ACTH was not
stimulated. We conclude that hypercapnia, associated with smaller decreases in pHa than that
in Experiment II, is not a stimulus to ACTH and is a mild stimulus to AVP. No hormone is
controlled by peripheral chemoreceptors. The afferent pathway for mediating ACTH, AVP
and PRA response to slow hemorrhage in fetal sheep needs to be investigated further.
xii


CHAPTER 1
INTRODUCTION
Various intrauterine stresses, such as hemorrhage, hypotension, hypoxia, acidemia and
hypercapnia, proved to stimulate ACTH, cortisol (Alexander et al., 1973; 1974b; Challis et al.,
1989), AVP (Rurak, 1979; Drummond et al., 1977; 1978) and renin (Zubrow et al., 1988;
Robillard et al., 1982) secretions in late gestational fetal sheep. Only a few experiments have
been done to investigate the specific afferent pathways for mediating the hormonal responses
to certain stresses. For example, the ACTH, AVP and renin responses to vena caval
obstruction were significantly correlated to the magnitude of the decrease in blood pressure
(Wood and Rudolph, 1983), and this response was mediated by afferent fibers in the carotid
sinus and/or aortic nerves (Wood, 1989a). The findings that the response of vasopressin to
hypoxemia is greater when the vagi are intact suggest a regulatory effect of the
chemoreceptors (Rurak, 1978).
Hemorrhage has long been used as a stimulus for investigating the cardiovascular and
endocrine responses to stress. In adult animals, the ACTH, cortisol and AVP (Wang et al.,
1983) responses to hypotensive hemorrhage have been shown to be mediated by cardiovascular
receptors located at the junction of the vena caval and atria, in the aortic arch, and in the
carotid vasculature (Brennan et al., 1971; Cryer and Gann, 1973; Gann et al., 1964; Share and
Levy, 1962; and Ludbrook, 1990). For mild or non-hypotensive hemorrhage, the mediator
for the hormonal responses proved to be atrial type-B receptors (Cryer and Gann, 1973; Wang
et al., 1983; Quail et al., 1987).
Fetuses have the ability to compensate more effectively for their volume depletion
than adults. A slow hemorrhage, which usually causes little or no change in arterial blood
1


2
pressure, can initiate large hormonal responses. It is suggested that these hormonal responses
are more important for fetal survival, because the fetal cardiovascular control mechanisms,
such as autonomic innervation of the heart (which is the major and most rapid regulator of
adult circulation), baroreflex and chemoreflex systems, etc., are not fully developed and fully
functioning in some species, even at term. It is important to further investigate the regulation
of hormonal responses to better understand the mechanism of fetal survival in intrauteral life,
as well as the cardiovascular and endocrine developmental procedures.
Reflex control of the fetal hormone secretion depends upon the adequate development
of related reflex components (sensors, afferent and efferent fibers and central nuclei) and the
maturation of the related endocrine organs or cells. Based on adult studies, the circulatory
reflex control system is very important to the hormonal responses mentioned above. We
assume that this is also important in fetuses.
The fetal afferent pathway for regulating hormonal responses to slow hemorrhage
remains unknown. The purpose of the studies in this dissertation is to investigate the afferent
pathway regulating ACTH, cortisol, AVP and renin responses to slow hemorrhage in late
gestational fetal sheep. Chapter 2 gives a background review of the developmental aspects of
the circulatory control and the maturation of the related endocrine organs. Chapter 3
describes the general methodology of the experiments involved. Chapters 4 and 6 evaluate
the effect of vagotomy (which interferes with the afferent fibers from atrial type B
receptors), and vagotomy plus carotid sinus denervation (which denervates the peripheral
baroreceptor and chemoreceptor afferent fibers) respectively, in fetal hormone responses to
slow hemorrhage; chapters 5 and 7 study the chemoreceptors effect on hormone responses
to severe and milder hypercapnic acidemia, which was induced by HC1 infusion in the former
and maternal hypercapnic mix-gas inhalation in the latter. Chapter 8 is a summary and
conclusion.


CHAPTER 2
BACKGROUND REVIEW
2.1 A Brief Review of the Fetal Circulatory System
The fetal cardiovascular system differs anatomically and functionally from the adult
system to meet the growth and developmental requirements of intrauteral life. There are two
circulations that are in parallel: the systemic and the umbilical-placental circulations. The
umbilical vein and arteries are vessels that connect these two circulations. The ductus venosus
carries most of the placental venous blood flow that bypasses the liver; the foramen ovale is
an opening between the right and left atria located in the interatrial septum; and the ductus
arteriosus is a vessel that connects the pulmonary trunk and the aorta. All these "designs" are
based on the fact that fetal alveoli are fluid-filled; the gastrointestinal tract and the kidneys
are much less functional than they become after birth. The two circulations ensure that the
fetus gets enough oxygen and nutrients to supply its growth and developmental requirement
and to eliminate waste products.
Compared to the adult, the most remarkable features of fetal cardiovascular functions
are the relatively higher cardiac output and heart rate (HR), which are 500 ml/kg/min and
150-180 bpm, respectively (Rudolph and Heymann, 1972; 1973), and lower mean arterial
pressure (MAP), which is 36-44 mm Hg (Yardley et al., 1983) in late gestational sheep fetuses.
The HR progressively falls and the blood pressure progressively increases in parallel with the
growth and development of the fetus. In fetal lamb, the HR was reported to fall 0.67
beats/min/day and the MAP was rise 0.46 mm Hg/day from 100 days of gestation (0.68 term,
term = 147 days) to term (Boddy et al., 1974b).
3


4
Fetuses have limited ability to increase their stroke volumes (Rudolph and Heymann,
1970; 1974; Rudolph et al., 1981). Examination of isolated fetal heart indicates that the heart
muscle cells are smaller and the amount of noncontractile mass is considerably greater in
fetuses than in the adults. Fetal sarcomeres are smaller in shape and are not well organized
(Friedman, 1973). The fetal resting or passive tension of the heart muscle is higher and the
compliance is much lower. The "stiffness" of the fetal heart restrict the performance of the
heart. Although previous consumption that fetal heart behaves at the upper limits of its
ventricular function curve (Gilbert, 1980) is proven to be incorrect because the influence of
the stroke volume by after load was ignored (Hawkins et al., 1988), the ability of the
increment of stroke volume in fetuses is still considered to be limited.
Almost half of the fetal cardiac output goes to the placenta through umbilical vessels.
It is known that umbilical vasculature is not under neural control, but vascular resistance can
be influenced by several vasoactive substances, such as angiotensin II, prostaglandins,
bradykinin, etc. (Mott and Walker, 1983). Placenta flow is also influenced indirectly by
systemic vascular tone. When systemic flow decreases or increases by vasoconstriction or
vasodilation, the placental flow increases or decreases respectively. However, under normal
physiological conditions, the fetus can always maintain an optimal flow ratio between these
two circulations. The mechanism by which the fetus maintains the appropriate balance
between placental and systemic circulations is not fully understood.
2.2 The Development of Autonomic Control of the Heart
The development of autonomic innervation of the fetal heart is the basis for the
appearance of baro and chemoreflex control of the circulation. Reports from studies of
rapidly developing chick embryos reveal that there are receptors and inactivating enzymes for
both parasympathetic and sympathetic nerves on day 2 (0.1 term, term=21 days); cholinergic
neuron growth within the sinoatrial node on day 6 (0.28 term); the first detectable release of


5
acetylcholine on day 10 (0.48 term), and the appearance of the functional vagal
neurotransmission, acetylcholine, and the acetylcholine synthetic enzyme, choline
acetyltransferase, on day 12 (0.57 term) (Pappano, 1977). Electrical stimulation of isolated
human fetal atria also caused release of acetylcholine, and depressed contractility of the heart
from 91 days of gestation (0.3 term). In fetal lambs, stimulation of the cervical vagus nerve
produced a small inhibition of the heart as early as 60 days of gestation (0.4 term) (Dawes,
1968). There is also evidence that effective parasympathetic neurotransmission develops in
guinea pig and rabbit fetuses (Vlk and Vincenzi, 1977). Myocardial innervation of the
sympathetic nerve in most species is found to be incomplete at birth (Friedman et al., 1968;
Lebowitz et al., 1972; Lipp and Rudolph, 1972). Sympathetic cardiac innervation in chick
embryos was proved by histochemical technique, which followed the same sequence of
cholinergic innervation, but the appearance of sympathetic nerves and the onset of effective
neurotransmission was delayed (Pappano, 1977). A similar sequence of autonomic
development occurs in man and other mammals, except the rat, which does not have cardiac
sympathetic nerves until about the end of the first week of life (Marvin et al., 1980; Vlk,
1979). These species differences of the development of the autonomic nerve system are
thought to correspond roughly to the general maturity of the animal at birth. The more
dependent the species are on their mothers at birth, the less well developed the system is. The
potential autonomic imbalance due to the delayed development of sympathetic nerves might
be compensated for by the earlier development of cardiac adrenergic receptors. In sheep
fetuses, /9-adrenergic receptors can be stimulated at about 60 days of gestation (0.4 term) by
appropriate agonists, which are ahead of the reported occurrence of sympathetic innervation
(Barrett et al., 1972) and in parallel to the reported earliest stage of the parasympathetic
stimulation (Dawes, 1968; Dawes et al., 1968). The point that greater development of
parasympathetic than sympathetic nerve control of the heart, even at end of fetal life, has
been very well proven and accepted.


6
2.3 The Development of Baroreflex Control of Circulation in Fetuses
Many efforts have been made to investigate the developmental aspects of arterial
baroreflex control of fetal circulation and it has long been known that these receptors are
active during fetal life. Two of the most common methods used in in vivo studies are: 1)
demonstrating the reflex HR responses following changes in arterial and/or carotid sinus
pressure, and 2) testing the HR response with or without intact baro-afferent nerve fibers.
As early as the 1940s, Barcroft reported a functional baroreflex in anesthetized and
exteriorized young fetuses in anesthetized ewes by injecting adrenaline and noradrenaline into
lamb fetuses (Barcroft, 1946). He extended his findings to goat, rabbit and sheep fetuses by
ligating their umbilical cords. The hypertension produced was associated with a significant
bradycardia. He also proved that this HR response was abolished by vagotomy. Since then,
numerous experiments in this area have been performed among different species.
It was found that the baroreflex was partially inhibited by carotid denervation and
totally abolished by subsequent aortic denervation during fetal life (Rudolph and Heymann,
1973), which suggests that these two nerve fibers are important for the responses. Rudolph
and his associates developed an unanesthetized, unstressed, and selectively peripheral
baroreceptor denervated fetal model (Itskovitz and Rudolph, 1982). Since then, the function
of these peripheral baroreflex afferent fibers has been better characterized. Baroreceptor
activity was also demonstrated directly by recording the impulse from nerve fibers. Biscoe
et al. (1969) measured phasic electrical activity in small bundles of fibers dissected from the
carotid sinus nerve in 120-147 days of gestation (0.8-0.99 term) fetal sheep, and Ponte and
Purves (1973) measured the activity in vago-afferent fibers in close-to-term sheep fetuses.
They found that the measured nerve activity is synchronous with the arterial pulse, suggesting
a functional baroreflex arc. Blanco et al. reported that spontaneous carotid and aortic


7
baroreceptor discharge is detectable from 85 days of gestation (0.6 term) in sheep fetuses
(Blanco et al., 1985).
However, the earliest stage of the fetal lamb that can be proven to present a functional
baroreflex control of the heart is 81 days of gestation (0.55 term) (MacDonald et al., 1980).
The baroreflex control of the heart rate matures with advancing gestation. This is
demonstrated by increased positive or negative HR responses to brief elevations or reduction
of arterial pressure, respectively. Shinebourne et al. (1972) studied fetal lambs from 85-145
days of gestation (0.6-0.99 term) and found that baroreflex sensitivity progressively increased
with advancing gestation until term. In younger fetuses, a sudden increase in aortic pressure
was associated only sporadically with a baroreflex response. When it was elicited, the response
was quite limited. Other studies also demonstrated that nearly all species experience a
progressive postnatal maturation of the reflex to adult levels (Gootman et al. 1979; Vatner and
Manders, 1979; Walker et al., 1990).
Further investigations tested the physiological role of baroreceptors in intrauterine
cardiovascular regulation. The baroreflex was considered unimportant for fetuses except
under conditions of elevated pressure, because the threshold of the reflex in adults is above
the range of the normal fetal arterial blood pressure. This point was challenged by Yardley
et al. (1979; 1983), who continuously recorded fetal arterial blood pressure during a 24-hour
period in both intact and sino-aortic denervated fetal lambs. He found that denervation
significantly increased the natural variability of arterial pressure. The coefficients of
variations of mean arterial pressure (defined as stand deviation of the mean arterial pressure
over the mean value of the mean arterial pressure) were twice as great in denervated fetuses
compared to intact ones. This result is similar to the result from another experiment
conducted by Cowley et al. (1973), who continuously recorded the BP within 24-hour on
active, unanesthetized adult dogs. Marked fluctuations in fetal basal arterial blood pressure
and heart rate after sinoaortic denervation were also observed by Itskovitiz et al. (1983),


8
although the MAP and HR are not different from control values. These results strongly
suggest that arterial baroreceptors have a natural role in day-to-day fetal arterial pressure
regulation.
Mechanoreceptors in atria, ventricles, and pulmonary arteries are potential sites of
cardiovascular reflexes that have not been systematically investigated in the fetus. In 1975,
Nuwayhid et al. (1975) reported that Bezold-Jarisch reflex could be stimulated by veritrodine
injection in lamb fetuses close to term (Wt > 2700 g). In their experiments, the assumption
that ventricular receptors affect fetal circulation was based on the reflex decrease of HR
response to decrease of arterial pressure (Oberg, 1976). It is known that in adult animals, HR
is accelerated by hemorrhage through arterial baroreceptor stimulation. In adult animals, only
very rapid and severe hemorrhage can produce bradycardia, which is mediated by the
increased firing rate of ventricular receptors that supersede the effect of arterial baroreceptors
(Oberg and White, 1970). In fetuses, tachycardia only occurs when blood pressure is mildly
reduced by hemorrhage or by venous occlusion (Wood et al., 1979; MacDonald et al., 1980).
With greater decrease in pressure, the transient increase in heart rate is reversed and
bradycardia occurs (Toubas et al., 1981; Wood and Rudolph, 1983a). Following atropine
administration the bradycardia is abolished, indicating vagal efferent involvement of the
reflex. These studies suggest that the ventricular receptor is functional during fetal life.
2.4 The Development of Chemoreflex Control of Circulation in Fetuses
In adult life, besides their dramatic effects on respiration, chemoreceptors are also
important in the control of circulation. The peripheral chemoreceptors are located in the
carotid and aortic bodies, and the central chemoreceptors are in the medulla oblongata. The
stimulation of the central chemoreceptors alone always results in a reflex tachycardia and a
very substantial increase in arterial blood pressure. Both effects are thought to be protective,


9
an attempt to circulate more blood through the affected areas in order to bring about a
decrease in carbon dioxide tension or an increase in oxygen tension. Also, it has been
suggested that the primary effect of carotid body stimulation in adult animals is bradycardia
(De Burgh Daly, 1972), and by contrast, the effect of aortic chemoreceptor stimulation
produces tachycardia (Sleight, 1974). The chemoreceptors of the aortic body in adults are
considered to be more important than those of the carotid body in circulatory regulation
(Comroe et al. 1964).
The aortic chemoreceptor was receptive to stimulation at about 100 days of gestation
(0.68 term) (Dawes et al., 1969a; 1969b). An increase in arterial blood pressure, a decrease
in HR, and vasoconstriction in the hind limb occured when arterial Pa02 and PaC02 was
changed over the physiological range, or when cyanide or nicotine was infused into fetal
lambs. These responses can be abolished either by vagotomy or aortic denervation (Baillie et
al., 1971; Dawes et al., 1969a; 1969b), which have specifically demonstrated the aortic
chemoreceptors effect. Direct recordings of fetal afferent electrical activity in aortic
chemoreceptor fibers (Ponte and Purves, 1973) reveal that the responses to asphyxia and
chemical stimulation are similar to those in the adults. The point that aortic chemoreceptors
are active and important for fetal cardiovascular regulation has been very well accepted.
Early reports from fetal carotid chemoreceptor studies are controversial. Some claim
that they are not functioning before birth, based on early direct nerve fiber recording studies
and acute hypoxia studies (Cross and Malcolm, 1952; Dawes et al., 1982, Boddy et al., 1974;
Dawes et al., 1969a; Purves and Biscoe, 1966), and some claimed that it is active based on
response to infusion of cyanide (Dawes et al., 1969b). Others observed that carotid
denervation showed no effect on fetal breathing movement, and only large quantities of
chemical stimulation of the carotid body affect fetal breathing movement (Jansen et al., 1981;
Purves, 1981). These results led to a conclusion that carotid chemoreceptor is inactive or
plays only a small part, if any, in intrauteral fetal life regulation. However, later studies, most


10
from chronic animal preparations, suggested that the carotid body was more active prenatally
than previously thought. Blanco et al. (1982) made direct recordings from carotid afferent
fibers in fetal sheep and found that a random activity at about 5 Hz occurred at a PaQ2 of 25
mm Hg. The firing rate was increased by retrograde injection of C02-saturated saline into
the lingual artery. Itskovitz and Rudolph (1987) performed carotid sinus denervation in sheep
fetuses at 120 days of gestation (0.8 term). The cardiorespiratory response to intracarotid
injection of cyanide was eliminated, which also supports the observation that carotid
chemoreceptors are functional during at least the last third of gestation. A resetting of the
chemoreceptor sensitivity on the day of birth and 5-10 days after birth was also reported
(Blanco et al., 1984; Hanson et al., 1986). The carotid chemoreceptor is actually more active
than previously thought.
Some reports indicate that direct stimulation of central chemoreceptors in fetal sheep
increases fetal heart rate (Jansen, 1975; Jansen and Read, 1977; Jansen etal., 1981). However,
most of the studies that test brainstem chemosensitivity of the brainstem in fetal lambs were
related to the regulation of fetal breathing movement. Ventricular-cisternal perfusion with
artificial cerebra-spinal fluid containing various concentrations of HC03- increased the depth
and incidence of breathing movements as CSF[H+] increased from 45 to 73 neq/L (Bissonnette
et al., 1980). A delayed fetal breathing movement was observed after intravenous infusion
of NH4+ and HC1, which can be attributed to slow penetration of the H+ into the interstitium
of the brain (Hohimer and Bissonnette, 1981). The developmental aspect of central
chemoreceptors and the interaction of the central and peripheral chemoreceptors during fetal
life need to be further studied.


11
2.5 Fetal ACTH. Cortisol. AYP and Renin Responses
2.5.1 ACTH and Cortisol
The structural and functional development of the hypothalamus-pituitary-adrenal axis
has been intensively investigated since 1960s. The glucocorticoids have been demonstrated
to play a vital role in fetal life in various species. Glucocorticoids are involved in the
maturation of several fetal organs or tissues, including the fetal lungs, adrenal medulla and
small intestine. Glucocorticoids also participate in initiating parturition, and in mediating
stress responses, which are important for fetal survival.
In human fetuses, the hypothalamus and pituitary are structurally showed to exist and
pituitary hormones in granules can be detected at 42 days gestation (0.18 term); the
hypothalamo-hypophysial portal system begins, and the releasing factors are identified at
about 49 days gestation (0.2 term). By 70 to 91 days of gestation (0.29-0.37 term), the
pituitary and hypothalamic tissues can respond in vitro to stimulatory or inhibitory stimuli.
By mid-gestation, the fetal hypothalamic-pituitary axis is functional and the feedback control
mechanism can be demonstrated. The pituitary-portal system presents as early as 49 to 56
days (0.2-0.23 term) and is complete at 126-140 days (0.53-0.58 term) in humans (Decherney
and Naftolin, 1980).
The early development of the hypothalamus and pituitary is also established in other
species, including sheep. Proopiomelanocortin (POMC), a precursor of ACTH and three other
peptides: pro-7MSH, 0-LPH and /3-endorphrin, were detected by an immunocytochemical
staining technique in the pituitary as early as 38 days of gestation (0.26 term) in sheep fetuses
(Mulvogue et al., 1986) and at 34 days (0.3 term, term = 114 days) in the porcine pituitary
(Dacheux, 1984). In the intermediate lobe of sheep fetuses, the POMC cells did not stain to
show positively until 60 days of gestation (0.4 term). From 70 days on (0.48 term), the
number of immunoreactive cells gradually increases, and by 90 days (0.61 term), almost all


12
the pars intermedia cells were intensely stained (Perry et al., 1985). Both "fetal" type
corticotrophs (cells that are unique to the fetal pituitary) and "adult" type corticotrophs, which
both contain POMC, were discovered in the fetal pituitary. Before 130 days (0.88 term), the
"fetal" corticotrophs were predominant cell types; then these cells gradually disappeared and
were replaced by the "adult" corticotrophs before term (Perry et al., 1985). By using ink
filling techniques, the hypothalamo-hypophysial blood system in sheep fetus was found to be
patent from 45 days gestation (0.31 term), which gives evidence that the pituitary is
potentially able to respond to hypothalamic releasing factors from this age onwards (Levidiotis
et at., 1989). The fetal pituitary is responsive to AVP stimulation, which causes it to secrete
substantial amounts of ACTH before the appearance of hypothalamic CRF. CRF terminals
cannot be identified immunocytochemically in median eminence until around 100 days of
gestation (0.68 term) (Levidiotis et al., 1987). AVP is present from 42 days (0.29 term), with
the majority of AVP fiber terminations being found in the external zone of the median
eminence. Norman and Challis (1987b) intravenously injected equimolar AVP and CRF into
sheep fetuses on days 110-115, 125-130,135-140 of gestation (0.75-0.78,0.85-0.88, and 0.92-
0.95 term, respectively). They found that the ovine fetal pituitary responds separately and
synergistically to AVP and CRF on days 110-115 (0.75-0.78 term), but the role of AVP in
stimulating ACTH release decreases with progressive gestational age. Plasma ACTH in sheep
fetuses has been detected as early as 59 days gestation (0.4 term) (Alexander et al., 1973b),
which also indicates the early functioning of the anterior pituitary gland.
The sheep fetal adrenal is morphologically recognizable by day 28 of gestation (0.19
term) (Ravault and Ortavant, 1977), while the zonation was not apparent until 60 days
gestation (0.41 term) (Maclsaac et al., 1989; Webb, 1980). The sheep fetal adrenal gland, a
highly active endocrine organ, is able to synthesize a considerable range of steroid hormones.
There are adrenal structural and functional differences in sheep fetuses as compared to
primates, including a permanent adrenal cortex instead of a fetal zone. This adult zone has


13
both 3-^HSD and A5 isomerase activities; thus the fetuses do not need to rely on the placental
source of progesterone for cortisol biosynthesis (Anderson et al., 1973). A slow, steady
growth of the fetal adrenal was observed between 80 and 135 days (0.54 and 0.91 term),
followed by explosive growth during the last 10-15 days of fetal life. This increase in weight
is almost entirely due to an increase in the size of the adrenal cortex, and within the cortex
the major growth occurs in the zona fasciculate (Comline and Silver, 1961; Liggins, 1969;
Nathanielsz et al., 1972). When comparing with the weight of the adrenal gland relative to
body size, the adrenals were maximal at an early stage of gestation (40-80 days, 0.27-0.54
term) in sheep fetuses (Wintour et al., 1975), 32 days (0.48 term, term=67 days) in guinea pigs
(Moog and Ortiz, 1957), and 84-140 days (0.35-0.58 term) in humans (Lanman, 1953; 1962).
Wintour et al. (1975) studied the adrenal function from 40 days gestation (0.27 term) in sheep
fetuses. They found that the cortisol output per g body weight was greater in the fetal adrenal
than the term adrenal when the adrenal glands were incubated with ACTH. The ACTH-
stimulated effect on cortisol secretion declined significantly from 91 to 120 days gestation
(0.62 to 0.82 term). Wintour et al. also measured peripheral blood level of cortisol in fetus
between 60 days and term sheep fetuses (0.41 to 0.99 term), plasma cortisol concentration was
significantly lower in 90-120 day fetuses (0.61-0.82 term) than in the younger or older ones.
These findings suggest that the fetal adrenal becomes relatively quiescent and partially loses
its sensitivity to ACTH after an early period of activity from 40 to 90 days gestation (0.27
to 0.61 term). This quiescent period is accompanied by a decrease in 17-hydroxylase and SCC
mRNAs in the inner zone of the cortex (Maclsaac et al., 1989). Studies show that the plasma
basal level of cortisol, accompanied by ACTH, starts to increase again 15-20 days before
parturition (Hennessy, et al., 1982; Maclsaac et al., 1985; Magyar et al., 1980 and Norman et
al., 1985). Some investigators divided the pattern of observed fetal plasma cortisol changes
from 120 days (0.82 term) to term into four phases: phase 1 is the initial phase of low plasma
cortisol concentration between 120-135 days (0.82-0.92 term) or so of gestation; phase 2 is 5-


14
13 days before delivery, which presents a slow initial increment of cortisol; phase 3 is a more
rapid increase that occurs between 5 days before delivery and in the last 12-24 hour of fetal
life; phase 4 is a very variable, final, stress-induced increment immediately before delivery
(Nathanielsz, 1976).
The dependence of the growth of fetal adrenal on pituitary factor, most likely ACTH,
was indicated by several studies. Hypoplasia of the fetal adrenal cortex (mainly in the zona
fasciculate) and a fall in fetal plasma corticosteroid concentration were observed after
electrocoagulation of the fetal sheep pituitary at 93 days gestation (0.63 term) (Liggins et al.,
1966; 1968; Nathanielsz et al., 1972). Infusion of ACTH into the fetus reversed the
deficiencies caused by hypophysectomy. The feedback regulation of cortisol on ACTH has
also been shown by infusion of cortisol into fetuses, which causes inhibition of ACTH
response to a variety of stimuli (Norman and Challis, 1987; Rose et al., 1985; Wood and
Rudolph, 1983b). Bilateral adrenalectomy and therefore removal of cortisol feedback leads
to an increase in fetal ACTH values after 125 days (0.85 term) (Wintour et al., 1980).
In terms of initiation of parturition, the fetal hypothalamo-hypophysial-adrenal axis
plays a major role in sheep. Experiments that interrupted the normal connection between the
fetal hypothalamus and pituitary by inserting a silicone plate between them, or by surgical
ablation of the fetal pituitary or adrenal, resulted in the prolongation of pregnancy with
failure of parturition to commence. Infusing ACTH or cortisol into the fetuses induced
premature delivery (Challis and Olson, 1988; Liggins, 1969; Liggins et al., 1973; MacDonald
and Porter, 1983; Thorburn and Charllis, 1979).
When the fetal hypothalamus-pituitary-adrenal axis response to stress are assessed
from the increase of plasma ACTH and cortisol concentrations, the other sources of the
hormone should be considered, including the placenta and the transplacental exchange. It is
known that ACTH can be produced by the placenta but the physiological role of placental
ACTH is uncertain. Although no change has been found in placental ACTH content as a


15
function of gestational age, placental ACTH can be stimulated under certain stress situations.
Jones et al. (1988) have suggested that CRF may be released from the ovine placenta in
response to the reduction of placental perfusion that results from /J-agonist administration.
Evidence from in vitro studies also indicate that CRF and ACTFt are localized in the placenta,
endometrium, and amnion (Challis JRG and Brooks AN, 1989). Carr et al. (1981) observed
that the concentration of ACTH in maternal plasma rose progressively during gestation,
independently of maternal glucocorticoids. This increase in ACTH might be from the
placenta, which lacks an effect on maternal adrenal.
The placenta is impermeable to peptides, including ACTH, AVP, renin, angiotensin
I and II, but is permeable to steroids, including cortisol. In another study, a five-hour
intravenous infusion of cortisol into pregnant ewes raised the maternal plasma cortisol from
12.2+4.2 to 44.0+7.0 ng/ml and the fetal plasma values increased from 3.9+1.5 to 12.0+4.5
ng/ml (Wood and Rudolph, 1984), suggesting a significant transplacental movement of cortisol
from mother to the fetus. A report from Dixon et al. (1970) also supports this conclusion.
However, these ability of cortisol to move transplacentally seems limited, because of the
presence of the diffusion resistance of the placenta to cortisol (Bietins et al., 1970; Liggins et
al., 1973). This diffusion resistance establishes a constant plasma cortisol concentration
gradient between ewes and their fetuses. Liggins et al. (1973) reported the resting gradient
is about 5 fold greater concentration in ewe plasma than in fetal plasma (14 and 3 ng/ml in
the ewe and fetus, respectively) by using isotope dilution techniques. Bietins et al. (1970)
calculated the transplacental movement of cortisol from fetus to ewe and showed that the total
contribution to the mothers by fetal plasma levels of cortisol is small. Since there is no
evidence to show that the cortisol transplacental movement is unidirectional, we assume that
cortisol can diffuse to the mother if the fetal cortisol concentration rises to a certain high level
above the maternal concentration. These data suggest that the fetal plasma cortisol


16
concentration is determined by both fetal adrenal production and the transplacental diffusion
movement, especially when the mother is under stress.
2.5.2 AVP
Vasopressin is synthesized in the supraoptic and paraventricular nuclei (SON and
PVN) of the hypothalamus via a precursor protein, called propressophysin, which is packaged
into neurosecretory vesicles within the neuronal perikaryon and enzymatically processed into
vasopressin, neurophysin, and a C-terminal polypeptide during axonal transport. The early
presence of vasopressin-generating cells can therefore be demonstrated by the precursor and
the other two peptides in addition to vasopressin. The axonal terminals spread along the
supraoptic-hypophyseal tract to the posterior pituitary, which is a storage terminal of the
hormone. Axons containing neurohypophyseal hormones also project to the median eminence,
where hormones can be secreted into portal vessels, and to other areas of the brain and spinal
cord.
Both SON and PVN are formed between 12-14 days gestational (0.57-0.67 term, term
= 21) in rats (Altman and Bayer, 1978a; Ifft et al., 1972) and mice (Shimada and Nakamura,
1973; Karim and Sloper, 1980). The neurons in these two species do not reach their mature
size until the fourth week postnatally (Dellmann et al., 1981; Khachaturian and Sladekm
1980). A quantitative study on the maturation of the rat SON was tested by vasopressin-
neurophysin antibodies (Khachaturian and Sladek 1980), showing that the neurophysin
positive cells were minimal initially, then gradually increased to 27% at 17 days gestation (0.81
term) and reached 46% and 65% at 20 and 22 days gestation (0.95-0.99 term). The cell sizes
also gradually enlarged to more adult-appearing cell bodies at end of gestation.
The ovine hypothalamo-neurohypophysial system is developed anatomically by 37-47
days gestation (0.25-0.32 term) (Diepen, 1941), and AVP is detected in the fetal lamb
neurohypophysis at 55 days (0.37 term) (Rurak, 1979) and in plasma at 59 days (0.40 term)


17
(Drummond et al. 1980). Although A VP concentration in fetal sheep pituitaries was found
to double between 90-143 days gestation (0.61-0.97 term) (Alexander et al., 1973b), the
resting plasma AVP concentration is normally very low, close to or somewhat lower than adult
levels (Alexander, 1974). It is unlikely that AVP is involved in normal circulatory regulation
with such a low plasma concentration. Early data suggest that the clearance rate of AVP is
higher in fetal lambs and rhesus monkeys than in adults (Allexander et al., 1976; Jones and
Rurak, 1976; Robillard and Weitzman, 1980). The placenta was originally considered to be
a major site of metabolism (Chard et al., 1973). However, when AVP metabolic clearance
rates and production rates were measured in chronically catheterized fetal, newborn, and adult
sheep by constant infusion, there was no significant difference among these three groups
(Stegner et al., 1984). Wiriyathian et al. (1983) and DeVane et al. (1982) giving evidence that
AVP was not cleared by the placenta.
It is known that in adult animals, AVP is important as an antidiuretic hormone, a
potent vasoconstrictor, and an ACTH-releasing factor. AVP release is stimulated by rising
blood osmolality or angiotensin II, by hypovolemia, and by a decrease in wall tension of the
left atrium. The antidiuretic, vasoconstrictive and central ACTH-releasing effects of AVP
have received much attention in developmental studies. It has been demonstrated in the past
few years that A VPs antidiuretic and vasoconstrictor effects were mainly important in
extreme situations during fetal life, such as during hemorrhage and hypoxia.
Hemorrhage is one of the most potent stimuli for AVP secretion. AVP can be
stimulated by massive hemorrhage as early as 59 days gestation (0.40 term) (Drummond et al.,
1980). A 10% reduction in blood volume in chronically catheterized fetal sheep aged between
96-124 days gestation (0.65-0.84 term) resulted in a rise in plasma AVP levels from 1.6+0.23
to 9.6+4.0 pg/ml, and a 20% loss produced levels of up to 31.7+14.7 pg/ml (Drummond et al.,
1980). Alexander (1971; 1974b) reported that the maximum AVP responses in fetal sheep can
be stimulated by less than 40% of hemorrhage. Hypotension caused by nitroprusside infusion


18
without changes of blood volume also stimulates AVP secretion (Zubrow et al., 1988).
Infusing the same amount of AVP as is produced by mild hemorrhage increased fetal blood
pressure, decreased fetal heart rate, and redistributed blood flow in chronically catheterized
fetal sheep (Iwamoto et al. 1979b). Kelly et al (1983) pretreated with vasopressin antagonist
A-(CH2)5Tyr(Me)AVP, found that 20% hemorrhage caused a significantly greater fall in BP
than fetuses without an AVP antagonist. But AVP antagonist pretreatment did not change the
basal fetal HR or MAP (Kelly et al., 1983). These results suggest that AVP is important for
fetuses in the regulation of blood pressure following hemorrhage in fetuses. However, the
unchanged basal HR and arterial pressure during AVP antagonist infusion suggest that AVP
may not have much involvement in daily regulation of fetal circulation.
2.5.3 Renin
Renin, an enzyme that can convert angiotensinogen to angiotensin I, is also detected
very early in fetal life. Renin has been extracted from the kidney of a 40-day gestational
fetal lamb (0.27 term) (Wintour et al., 1977) and 22 days (0.19 term) from a pig fetus (Kaplan
and Fridman, 1942). The lamb fetal plasma renin concentration was lower than maternal
levels from 90 to 104 days gestation (0.61-0.70 term) (Carver and Mott, 1975), and
progressively increased toward term. In the last quarter of gestation, the plasma renin
concentration reached a level that is significantly higher in the fetal lambs than in their
mothers (Broughton Pipkin and OBrien, 1978; Broughton Pipkin et al., 1974a). Plasma renin
activity (PRA), which is determined as the initial production rate of angiotensin I from
angiotensinogen during incubation of plasma in vitro, was found consistently higher in
chronically catheterized fetal lambs than in the ewes (Broughton-Pipkin and OBrien, 1978;
Broughton Pipkin et al., 1974a; Fleischman et al., 1975; Smith et al., 1974).
The high activity of the renin-angiotensin system in unstressed fetuses suggests that
this system is important in regulating fetal circulation under physiological conditions.
Infusion of Saralasin, a specific angiotensin receptor-blocking agent, into fetal lambs, resulted


19
in a fall in blood pressure, and the changes of blood pressure were linearly correlated to the
initial angiotensin II level (Broughton-Pipkin and OBrien, 1978). A rapid fall in fetal blood
pressure was also observed when converting enzyme blocker captopril was administered to the
mother. This fall in fetal blood pressure lasted for up to 3 days (Broughton-Pipkin et al.,
1982). Hyman et al. (1975) found that chronic unilateral renal artery constriction in fetal
lambs was associated with a marked elevation in both fetal plasma renin activity and arterial
blood pressure. In addition to the effect on blood pressure, infusion of angiotensin II
inhibitors to unstressed fetuses also decreased placenta flow (Iwamoto and Rudolph, 1982).
Due to the immaturity of the fetal cardiovascular regulation system, it is possible that renin-
angiotensin system plays a more important role in regulating circulation physiologically than
it does in adults.
Hemorrhage in both anesthetized and unanesthetized fetal lambs, even as little as 3%
of the calculated fetal blood volume, has been shown to stimulate PR A in fetuses from 110
days gestation to term (0.75 term) significantly (Broughton-Pipkin et al., 1974a; 1974b; Smith
et al., 1974). In another study, a 12 ml hemorrhage stimulated PRA in 3 out of 5 anesthetized
fetal piglets on 85 days of gestation (0.75 term). By 111 days (0.97 term), PRA increased in
all eight piglets studied (Broughton Pipkin et al., 1981). Iwamoto and Rudolph (1981b)
reported that previous administration of saralasin blocked the fetal lambs ability to restore
its blood pressure and heart rate following hemorrhage. These studies suggest that
hemorrhage is as least as strong a stimulus for fetal renin secretion as it is in adults.
2.6 Summary
1.
The fetal cardiovascular system differs anatomically and functionally from the adult
to meet its growth and developmental requirements in intrauterine life.


20
2. The autonomic system starts to function at least before the end of the first half
gestation, and the parasympathetic nerve system is more developed than the
sympathetic nerve system at term.
3. Fetal baro and chemoreceptors undergo a development sequence and are active at the
second half of gestation.
4. The ventricular receptors function in late gestational fetal sheep.
5. The fetal hypothalamus-pituitary-adrenal axis is active in the first trimester of fetal
life. The adrenal becomes refractory to ACTH stimulation in the middle third of
gestation, which is accompanied by a decrease in 17-hydroxylase and SCC mRNAs
in the inner zone of the cortex. After this period, the adrenal becomes increasingly
responsive to ACTH, and both ACTH and cortisol concentration in plasma increase
shortly before term and reach their peaks at parturition.
6. The hypothalamo-neurohypophysial system appears to be anatomically developed by
the first quarter of gestation. AVP acts as an early ACTH-releasing factor before and
after the CRF is functional. AVP is important for responses to hypotension, but not
for basal circulatory regulation in fetuses.
7. The renin-angiotensin system is important in regulating fetal circulation under both
physiological and pathological conditions.
8. The placenta can produce ACTH and CRF and is permeable to corticosteroids but not
to ACTH, AVP, and renin.
9. The fetuses respond to hemorrhage with an increase in ACTH, cortisol, AVP, and
PR A. In adult animals, the afferent pathway for the hormone responses to mild- or
non-hypotensive hemorrhage is mediated by atrial type-B receptors which is linked
to vagus afferent fibers. The afferent pathway for fetal hormone secretion to slow
hemorrhage remains unknown.


CHAPTER 3
GENERAL METHODOLOGY
3.1 Surgical Procedures of Catheterization and Denervation
All surgeries were performed at least four days before the experiments. For 24 hours
before surgery ewes were not fed but were allowed free access to water. During surgery ewes
were anesthetized with 1.0-2.5% halothane in oxygen. Using strictly aseptic techniques, we
exposed the uterus with a midline incision. After incising the uterus, a fetal hind limb was
delivered and a polyvinylchloride catheter (0.030 in. i.d., 0.05 in O.d.) was inserted into the
tibial artery. A larger catheter (0.040 in. id.,0.070 in. o.d.) was inserted into the saphenous
vein. After catheterization of these two vessels, the fetal skin was sutured and the hind limb
was returned to the amniotic cavity. Then the second fetal hind limb was delivered and the
procedure was repeated. A polyvinylchloride catheter (0.050 in.i.d., 0.090 in.o.d.), with side-
holes cut into the tip, was sutured to the skin before returning the second hind limb to the
amniotic cavity. The amniotic catheter was used for measuring amniotic fluid pressure during
experiments. The uterus was closed.
The surgical procedure for vagotomy and carotid sinus denervation was similar to that
described by Itskovitz and Rudolph (1982). Briefly, after making another incision in the
uterus, the fetus head was delivered. A midline incision was performed in the fetus neck
near the angle of the jaw, the occipital-carotid arterial junctions were carefully exposed. The
carotid sinus nerves, the IXth cranial nerves and the vagosympathetic trunks were in turn
identified and sectioned as required. The superior thyroid arteries were ligated and cut, as
were all branches of the common carotid arteries between the superior thyroid and lingual
21


22
arteries, to ensure sections of the common carotid nerves. The walls of the common carotid
arteries in this area, as well as the lingual arteries and common carotid arteries extending 0.5-
1 cm rostral from the lingual-carotid arterial junction, were stripped off all visible nerve
fibers. The fetal skin was closed.
After closing the incision in the uterus, 500 mg ampicillin (Polyflex, Veterinary
Products, Bristol Laboratories, Syracuse, New York) was injected into the amniotic fluid.
Catheters were filled with heparin (1,000 units/ml; Wilkins-Sinn, Cherry Hill, New Jersey),
plugged, and threaded out through a stab wound in the flank where they were protected by
a cloth pouch sutured to the skin. In the case of twins, both fetuses were catheterized.
After the completion of the abdominal surgery, polyvinylchloride catheters (0.050
in.i.d., 0.090 in.o.d.) were inserted into the maternal femoral artery and vein at the level of
the femoral triangle, and the tips were advanced to the abdominal aorta and inferior vena
cava, respectively. The catheters also were filled with heparin, plugged, and routed
subcutaneously to the flank, where they were protected by the same pocket as the fetal
catheters. 500 mg ampicillin was injected intramuscularly into the mother at the time of
surgery as well as once per day for five days after surgery. Fetuses were also treated with 500
mg ampicillin via the amniotic fluid catheter once every day for five days and after each
experiment. All catheters were flushed and reheparinized at least once every 3 days.
3.2 General Preparation for Experiments and Hemodynamic Data Collection
The pregnant ewes used in all the experiments were mixed Western and Florida Native
breeds. In the 2 series of hemorrhage studies, the animals participated in only one
experiment. For those animals participating in more than one experiment in the other two
studies (HC1 infusion and hypercapnia), at least 48 hours were allowed between experiments,
and the order of the experiments was randomized. No fetus was subjected to the same
protocol more than once. All experiments were started between 0900 and 1100 hours to


23
prevent possible rhythm variations between animals in resting hormone concentrations or in
the magnitude of stimulated responses.
On the morning of the experiment, the ewe to be studied was transported from the
Health Center Animal Resources Department to the laboratory. At least one hour was allowed
before the experiment started to let the ewe acclimate to the laboratory environment. During
this time, one fetal femoral artery, vein, and the amniotic fluid catheter were connected to
the transducers (Statham P23 Db or P23Id transducers, Statham Instruments, Oxnard,
California) for measurement of intravascular and amniotic fluid pressures. Pressures were
measured continuously using a Beckman R611 (Beckman Instruments, Schiller Park, Illinois)
or Grass Model 7 (Grass Instruments, Quincy, Massachusetts) direct-writing recorder. Fetal
heart rate was measured using an appropriate Beckman or Grass cardiotachometer triggered
from the arterial pressure signal. Mean femoral arterial pressure was recorded as the damped
mean of the phasic signal. Analog voltage outputs of the amplifiers were sampled by a
Keithley DAS analog-to-digital converter (Keithley System 500, Keithley Data Acquisition
Control, Cleveland, Ohio) and IBM AT microcomputer at a rate of 0.5 Hz. The variables were
sampled and analog-to-digital conversions performed at 2-second intervals and stored on
floppy disk. Intravascular pressures were corrected by subtraction of amniotic fluid pressure
off-line. All fetal intravascular pressures were calculated using amniotic fluid pressure
as zero reference.
3.3 Handling and Analysis of Blood Samples
All blood samples were placed in chilled plastic centrifuge tubes containing 0.05 ml
of 0.3 M Na4EDTA (Sigma Chemical Co, St. Louis, Missouri) per ml blood. All tubes were
kept on ice until the end of the experiment, when they were centrifuged at 3,000 g for 20


24
minutes in a refrigerated (4C) centrifuge. The plasma was stored at -20C until hormones
were assayed.
PRA was measured using a modification of the method by Haber et al., (1984). The
kit was from Clinical Assays. For this assay, angiotensin I was generated in buffered (pH 5.7)
plasma in vitro for one hour at 37C. At the end of the incubation period the angiotensin I
concentration was measured by RIA. This method has been described in detail elsewhere
(Wood et al., 1989b).
Plasma cortisol concentrations were measured by RIA using antiserum No. 1460 (lot
R2) from Radioassay Systems Laboratories (Carson, California) and [3H]-[l,2,6,7]-cortisol
from New England Nuclear Corp. (Boston, Massachusetts) or Amersham Co. (Arlington
Heights, Illinois). Plasma was deproteinized with 50-100 vol of ethanol before assay.
Plasma ACTH was measured by radioimmunoassay (RIA) in either unextracted plasma
(in the first two series of studies) or extracted plasma (in the last two series of studies, using
powdered glass, eluted with HC1 and acetone). The former used anti-ACTH antiserum and
hACTH-(l-39) supplied by the National Hormone and Pituitary Program. The 125I-ACTH
used in this assay was made by iodination of the hACTH-(l-39) standard by the chloramine-
T method (Rees et al, 1971). The latter used both anti-ACTH raised in this laboratory and
1-39 hACTH standard, which was supplied by the National Hormone and Pituitary Program
(NIDDK, University of Maryland School of Medicine). This antiserum cross-reacts 100%
with (1-24)-ACTH, 11-24 ACTH, and l-39hACTH, but does not bind oCRF or methionine
enkephalin.
Plasma vasopressin (AVP) concentrations were measured by RIA using anti
vasopressin antiserum purchased from Amersham, 125I-vasopressin from New England
Nuclear, and synthetic arginine vasopressin from Sigma.
In the first two series of experiments, plasma assayed for AVP was an extract of
acetone as described by Cowley and co-workers (Cowley et al., 1981). In the last two series


25
studies, the plasma was extracted using bentonite, eluted with a 1:1 mixture of 1 M HC1 and
acetone. Extracts were dried using the Speedvac concentrator. The antiserum bound arginine
vasopressin 0.5% relative to 1-39 hACTH.
Fetal blood gases were measured using a Radiometer PHM73 blood gas analyzer and
BMS3Mk2 blood microsystem (Radiometer, Copenhagen, Denmark). The blood gas analyzer
was calibrated as recommended by the manufacturer using two reference gas mixtures, one
containing 8% C02, 21% 02, and the balance N2, and the other containing 5% C02 and the
balance N2 (Radiometer). Plasma protein concentration was measured by refractometry in
study 3 (Chapter 6). Plasma sodium and potassium concentrations were measured using a
NOVA 1 sodium/potassium analyzer (Nova Biomedical, Waltham MA).
3.4 Calculations and Statistical Analyses
The data were analyzed by two-way analysis of variance (ANOVA) corrected for
repeated measures in one dimension, time (Winer, 1971). Changes were assessed within
groups in some studies using one-way ANOVA for repeated measures. A posteriori
comparison of individual means was performed using Duncans multiple range test (Winer,
1971). Initial fetal and maternal variables were either tested by Students t-test or by one-way
ANOVA. In Experiment I (Chapter 4), correlations among variables were tested using
standard correlations analysis. A significant level of p<0.05 was used to reject the null
hypothesis in all tests.


CHAPTER 4
THE ROLE OF VAGOSYMPATHETIC AFFERENT FIBERS
IN THE CONTROL OF ACTH, VASOPRESSIN, AND RENIN RESPONSES
TO HEMORRHAGE IN FETAL SHEEP
4.1 Introduction1
In adult animals, hemorrhage stimulates secretion of ACTH (Redgate, 1968),
corticosteroids (Farrell et al., 1956; Gann, 1969), renin (Sapirstein et al., 1941), and A VP
(Ginsburg and Heller, 1953) mediated via cardiopulmonary (Cryer and Gann, 1973; Brennan
etal., 1971) and arterial mechanoreceptors (Redgate, 1968; Gannetal., 1964; Share and Levy,
1962). Renin is controlled by mechanoreceptors in those areas and by the intrarenal
baroreceptor and the macula densa (Davis and Freeman, 1976). All three of these hormone
systems also respond to hypoxia and/or hypercapnia, responses that may be at least partially
mediated by the peripheral chemoreceptors (Raff et al., 1983a; 1983b; 1984). Results of
experiments in adult animals suggest that atrial or other cardiac receptors with
vagosympathetic afferent fibers are of primary importance in the control of ACTH, A VP, and
renin responses to small or moderate hemorrhage (Cryer and Gann, 1973; Wang et al., 1983;
Quail et al., 1987).
Fetal sheep respond to hemorrhage with increases in plasma ACTH (Alexander et al.,
1973; 1974; Rose et al., 1978), AVP (Robillard et al., 1979; Rurak, 1979; Ross et al., 1986;
Brace and Cheung, 1986), and renin (Robillard et al., 1982) concentrations. Presumably,
receptor populations in the fetus that control the secretion of these hormones are similar to
1 This work was in part supported by the National Institute of Health grants HD-20098
and HL-36289.
26


27
those in the adult. One might predict that, in the fetus as in the adult, the hormonal responses
to a nonhypotensive or mildly hypotensive hemorrhage would be attenuated by interruption
of the vagosympathetic afferent fibers from atrial or other cardiopulmonary receptors. This
study was designed to investigate this possibility.
4.2 Materials and Methods
Ten chronically catheterized pregnant ewes and their fetuses were studied. One sheep
carried twins; the others carried single fetuses. On the day of study, the fetuses were between
128 and 133 days gestation.
Six fetal sheep (including the twins) were prepared with vascular catheters only. Five
fetal sheep were subjected to bilateral section of the cervical vagosympathetic trunks.
Eleven ml blood samples were withdrawn from a fetal arterial catheter at 10-minute
intervals for 120 minutes. At the beginning (0 minute) and end (120 minutes) of each
experiment, 5 ml blood samples were drawn from the maternal arterial catheter. This
hemorrhage paradigm is similar to that used by Brace and Cheung. Fetal blood gases were
measured in all experiments.
4.3 Results
Initial fetal pHa values were 7.39+.02 and 7.39+.01, Pa02 22.3+1.4 and 24.0+1.5 mm
Hg, and PaC02 43.3+1.3 and 42.0+1.1 mm Hg in the intact and vagotomized groups,
respectively. None of these values were significantly different between groups.
Overall, hemorrhage decreased MAP (Figure 4-1, left). There was no significant
difference in the MAP response to hemorrhage in the two groups. HR (Figure 4-1, right) was
not significantly altered by the hemorrhage. Vagotomy did alter the CVP response to the


Mean Arterial Pressure (i
28
cn
I
E
E
60-
50-
40-
30.
60
50
40
30
Time (min from
250
225
200
175
150
250
225
200
175
150
onset of hemorrhage)
Figure 4-1. MAP and HR during hemorrhage in fetal sheep that were intact or
subjected to bilateral section of cervical vagosympathetic trunks.
Heart Rate (bpm)


29
hemorrhage (Figure 4-2).
CVP significantly decreased in intact fetuses during hemorrhage. Hemorrhage
significantly decreased fetal pHa (Figure 4-3, bottom panel). The pHa decreased more rapidly
in the vagotomized group. In similar fashion, PaC02 (Figure 4-3, middle) increased
significantly, but more rapidly in the vagotomized group. PaQ2 (Figure 4-3, top) decreased
similarly in both groups equally.
Hematocrit (Figure 4-4) was significantly lower in the vagotomized fetal sheep at the
beginning of hemorrhage (42+2% vs. 37+2% packed cell volume [PCV] in intact vs.
vagotomized fetuses). The magnitude of the decrease in hematocrit during the course of the
hemorrhage was greater in the intact fetuses (mean change, 6 % PCV) than in the vagotomized
fetuses (mean change, 4 % PCV). Because the fetal sheep does not have a contractile spleen,
acute changes in Hct have been used to calculate changes in blood volume (Brace, 1983). In
the present experiments, the decrease in Hct during the hemorrhage may have been caused
by transplacental and transcapillary refilling of the fetal vascular space. Red cells were
diluted 14% in the intact group and 12% in the vagotomized fetuses, suggesting a more
effective defense of blood volume in the intact group.
Initial fetal plasma ACTH concentrations were 41+8 and 60+7 pg/ml and initial fetal
plasma cortisol concentrations were 9.1+3.3 and 7.8+2.2 ng/ml in the intact and vagotomized
fetuses, respectively (Figure 4-5). Initial values of ACTH and cortisol were not different in
the two groups. Hemorrhage stimulated similar ACTH and cortisol responses in both groups.
Initial fetal plasma AVP concentrations were 2.7+0.3 and 2.6+0.3 pg/ml and initial
fetal PRAs were 5.0+1.5 and 4.7+2.2 ng angiotensin I/ml/hr (Figure 4-6). These initial values
of vasopressin concentration and PRA were not different in the two groups. Hemorrhage
stimulated similar AVP and similar PRA responses in the two group correlations of fetal
plasma ACTH and AVP concentrations and PRA to fetal MAP, CVP, and pHa were tested
(Table 4-1). Logarithms of fetal hormone concentrations and activities were used in the


Central Venous Pressure
30
Time (min from onset of hemorrhage)
Figure 4-2. CVP during hemorrhage in fetal sheep that were intact or subjected to
bilateral section of cervical vagosympathetic trunks.


31
Figure 4-3. PaG2, PaC02, and pHa during hemorrhage in fetal sheep that were intact
(open circles) or subjected to bilateral section of cervical vagosympathetic trunks
(filled circles).


Time (min from onset of hemorrhage)
Figure 4-4. Hct during hemorrhage in fetal sheep that were intact (open circles)
subjected to bilateral section of cervical vagosympathetic trunks (filled circles).


Fetal Plasma Cortisol (ng/ml) Fetal Plosma ACTH (P9/ml)
33
1000
800
O O INTACT
VAG0T0MIZED
600
400
200
V
^ <>/-<>
.' o
Figure 4-5. Plasma ACTH and cortisol concentrations in fetal sheep that were intact
(open circles) or subjected to bilateral section of cervical vagosympathetic trunks
(filled circles).


Fetal PRA (ng Al/ml/hr) Retal Plasma AVP (pg/ml)
34
o o INTACT
VAGOTOMIZED
12
10
0 1 * 1 1 1 1 1 1 1 i i i i
35
0 1 1 1 1 1 1 1 1 i i i i i
o 20 40 60 80 100 120
Time (minutes after onset of hemorrhage)
Figure 4-6. Plasma AVP concentration and PRA in fetal sheep that were intact (open
circles) or subjected to bilateral section of cervical vagosympathetic trunks (filled
circles).


Table 4-1. Values of correlation Coefficients Relating Fetal Plasma Hormone Concentrations
to Arterial pH, MAP, and CVP.
LogtACTH) versus
Log(AVP) versus
Log(PRA) versus
pH
MAP
CVP
pH
MAP
CVP
pH
MAP
CVP
Intact Fetuses
GI7
-0.83*
0.39
-0.57*
-0.73*
0.44
-0.41
-0.72*
0.41
-0.53*
N407
-0.82*
0.36
-0.66*
-0.82*
-0.82*
0.02
-0.92*
0.33
-0.66*
0O74A
-0.93*
-0.23
0.02
-0.83*
0.07
0.23
-0.85*
-0.31
0.12
0074B
-0.56*
a
a
-0.43
a
a
-0.54*
a
a
0071
-0.64*
-0.15
0.52
-0.64*
-0.18
0.64
-0.44
-0.39
0.64
Y70
-0.28
-0.75*
0.74
b
b
b
-0.29
-0.72*
0.74
Vagotomized fetuses
Y5I -0.99*
-0.69*
-0.66*
-0.91*
-0.73*
-0.73*
c
c
c
0247
-0.98*
-0.13
d
-0.98*
-0.10
d
-0.90*
-0.32*
d
Y63
-0.73*
-0.49
-0.19
-0.40
-0.36
-0.23
-0.84*
-0.40
0.16
Y64
-0.87*
-0.04
-0.30
0.55
0.26
0.61
-0.86*
-0.16
-0.60
Y236
-0.94*
-0.57*
-0.37
-0.83*
-0.47*
-0.34
-0.97*
-0.77*
-0.51
a, No hemodynamics in this experiment; b, no AVP measurements in this experiment, c. no
PRA measurements in this experiment; d, no central venous pressure in this experiment.
p<0.05.


36
correlations because logarithmic transformation linearized the relations (for example, see
Wood et al., 1982). In one intact fetus, plasma ACTH was significantly related to MAP and
CVP, and PRA was related to MAP. In one other intact fetus, vasopressin was significantly
related to MAP. In one vagotomized fetus, ACTH and vasopressin were significantly related
to both MAP and CVP, and in another vagotomized fetus, ACTH and PRA were significantly
correlated to MAP (Table 4-1). Interestingly, in some of the experiments, ACTH,
vasopressin, or PRA were correlated to increases in central venous pressure (e.g., fetuses
Nos.0071, Y70, and Y64). In contrast to the inconsistent or seemingly inappropriate
(increasing hormone concentrations with increasing intravascular pressures) correlations
between hormone concentrations and arterial or venous pressures, the hormone responses were
much better correlated to the changes in pHa (Table 4-1). In 12 of 14 possible comparisons
in intact fetuses and in 13 of 18 possible comparisons in vagotomized fetuses, correlations
between hormone response and change in pHa were significant. The mean values of fetal
plasma ACTH, A VP, and PRA are graphically summarized in Figure 4-7. The relation
between ACTH or vasopressin concentration or PRA and pHa appeared to differ in the two
groups (Figure 4-7). However, there was more variability in the slopes within groups than
between groups. For this reason, there was no significant difference in the slopes between
the two groups. Shown in Figure 4-8 are the distributions of correlation coefficients relating
pHa, MAP, and CVP to the logarithm of plasma ACTH, AVP, and PRA.
Maternal plasma hormone concentrations were measured at the beginning of each
experiment. Maternal plasma ACTH concentrations were 102+39 and 151 + 14 pg/ml, and
plasma cortisol concentrations were 12.3+4.8 ns 16.1+3.7 ng/ml in the groups with intact and
vagotomized fetuses, respectively, Maternal plasma AVP concentrations were 2.5+0.1 and
2.9+0.3 pg/ml, and PR As were 2.9+0.7 and 2.4 +1.1 ng angiotensin I/ml/hr in the intact and
vagotomy groups, respectively. There were no statistically significant differences in maternal
plasma hormone levels in the two groups (tested by t test for independent groups).


37
1000
100 T
Figure 4-7. Relations among mean values of pHa and mean values of fetal plasma
ACTH and AVP concentrations and PRA.


Correlation Coefficient (r)
38
pH MAP CVP
I
Figure 4-8. Distribution of r values of fetal pHa, MAP. and CVP vs Lg ACTH (open
circles), AVP (filled circles), or PRA (open triangle). Symboles at the extremes and
inside box are the range of distribution and median values.


39
4.4 Discussion
The results of this study suggest that the control of hormonal responses to hemorrhage
in fetal sheep is different from that in the adult. Section of the cervical vagosympathetic
trunks, which interrupt afferent fibers from atrial and ventricular mechanoreceptors, did not
alter the magnitudes of the ACTH, AVP or PRA responses to hemorrhage. In adult
anesthetized dogs, acute vagotomy attenuated the vasopressin (Share, 1967) and adrenal
corticosteroid (Gann and Cryer, 1973) responses to nonhypotensive or mildly hypotensive
hemorrhage. ACTH and AYP in the adults are inhibited by afferent impulses from the atrial
mechanoreceptors with afferent fibers in the vagus nerves (Brennan et al., 1971; Baertschi et
al., 1976) and from carotid arterial mechanoreceptors (Gann et al., 1964; Share and Levy,
1962; Wood and Rudolph, 1983; Wood et al., 1985). Renin is controlled by these receptors and
by the intrarenal baroreceptor (reviewed by Davis and Freeman, 1976).
The cardiopulmonary receptors are quite important in the mediation of the ACTH and
AVP responses to slow or otherwise mild hemorrhage in adult animals. Renin responses to
hemorrhage are less dependent on the activity of the cardiopulmonary receptors. Adrenal
corticosteroid responses to 5 ml/kg hemorrhage in anesthetized dogs are attenuated by
simultaneous inflation of a balloon in the right atrium (Cryer and Gann, 1973). Blockade of
cardiopulmonary receptors with intrapericardial injections of procaine blocked the vasopressin
but not the renin response to hemorrhage of a volume of up to 35% of blood volume in
conscious rabbits (Quail et al, 1987). Similarly, cardiac denervation attenuated the vasopressin
response but not the renin response to 10, 20, or 30 ml/kg hemorrhage in conscious dogs
(Wang et al., 1983). While afferent information from arterial mechanoreceptors may
contribute to the ACTH, AVP, and renin responses to hypotensive hemorrhage, the
cardiopulmonary receptors appear to be most important. AVP and renin responses to


40
progressive hemorrhage to 35% of blood volume in conscious rabbits were not attenuated by
sinoaortic denervation (Quail et al., 1987). ACTH and corticosteroid responses to hemorrhage
in sinoaortic denervated lambs were not smaller than responses in intact lambs (Wood et al.,
1985). Chemoreceptors may influence the secretion of ACTH, A VP, and renin in adult
animals during hypoxia and/or hypercapnia (Raff et al., 1983a; 1983b; 1984), however,
chemoreceptor stimulation is unlikely to mediate the responses of these hormones to small or
moderate hemorrhage because carotid sinus denervation (which would eliminate afferent
fibers from carotid arterial chemoreceptors and baroreceptors) does not attenuate the ACTH,
AVP, or renin responses to hemorrhage in postnatal lambs (Wood et al., 1985).
Responses to hemorrhage in fetal animals differ from responses in adult animals in
that moderate hemorrhage produces acidemia in addition to alterations in arterial and/or
venous pressures (Toubas et al., 1981). The fetal acidemia is a respiratory acidemia caused
by a primary increase in fetal PaC02. This condition, analogous to hypoventilation by the
adult, is most probably caused by decreased perfusion of the umbilical-placental circulation.
Microsphere studies have demonstrated that hemorrhage reduces umbilical-placental perfusion
(Itskovitz et al., 1982).
Fetal animals differ from adult animals in that MAP is regulated at a lower level.
Chronic sinoaortic denervation in fetal sheep increased the variability of blood pressure and
heart rate, indicating that fetal arterial baroreceptors are active at the regulated level of
arterial pressure (Itskovitz et al., 1983). However, the firing rates of the fetal arterial
baroreceptors may be at or near the threshold for activation. If this were true, fetal arterial
baroreceptors would be less responsive to decreases than increases in fetal arterial pressure.
Fetal arterial PaQ2 is also regulated at a somewhat lower level than that in the adult. It is
known that fetal peripheral chemoreceptors are active at this low PaQ2 and that the sensitivity
of these receptors to changes as arterial oxygen tension resets after birth to adult levels


41
(Blanco et al., 1984). Little is known about the characteristics of atrial receptors in fetal
animals.
Several studies have demonstrated that fetal sheep respond to hemorrhage with
increases in plasma ACTH and cortisol (Rose et al., 1978), AVP (Rurak, 1979), PRA,
angiotensin II, and aldosterone (Robillard et al., 1982). It is known that the secretion of these
hormones is influenced by induced changes in arterial or venous pressure. For example,
ACTH and AVP are stimulated by vena caval obstruction in fetal sheep, and the magnitude
of the responses is related to the severity of the obstruction (Wood et al., 1985), leading to the
speculation that cardiovascular mechanoreceptors influence the secretion of these hormones.
During hypovolemia in fetal sheep, plasma AVP and PRA responses correlated better to the
volume of the hemorrhage than to the induced changes in MAP, leading to the speculation
that volume receptors are important in the control of these two hormones (Robillard et al.,
1979). A significant correlation between plasma AVP and pHa during hypovolemia was noted
in one study (Rurak, 1979). Other investigators have suggested that fetal hypoxia during
hypovolemia may contribute to the vasopressin response (Ross et al., 1986). While several
groups of investigators have studied hormonal responses to hemorrhage in the fetus, the
populations of cardiovascular receptors responsible for mediation of these hormonal responses
have received little attention.
As in studies by other investigators, the fetal hormonal responses to hemorrhage were
not well correlated to the induced changes in arterial pressure (Robillard et al., 1982; Brace
and Cheung, 1986). It is apparent from the results of the present study that fetal ACTH,
AVP, and renin responses to mildly hypotensive hemorrhage in fetal sheep are more closely
associated with the induced changes in arterial blood pH. The correlations with arterial and
central venous blood pressure reveal mostly either nonsignificant relations or relations that
are seemingly inappropriate for cardiovascular mechanoreceptor-hormone relations (increased
hormone concentration with increased blood pressure). In contrast, the correlation


42
coefficients calculated from relations between hormone concentrations and pHa are high in
most experiments. The association of hormone response to changes in pHa would therefore
suggest the possibility that the responses of these hormones to mild hemorrhage in the fetal
sheep are mediated by the peripheral chemoreceptors rather than mechanoreceptors. It is also
possible however, that the hypercapnia produced by fetal hemorrhage stimulated the hormonal
responses via medullary chemoreceptors. Raff and co-workers (Raff et al., 1984)
demonstrated that deafferentation of the carotid chemoreceptors attenuated that ACTH and
corticosteroid response to isocapnic hypoxia but had no effect on the responses to hypercapnic
hypoxia in anesthetized adult dogs.
While vagotomy did not alter the final magnitudes of the fetal ACTH, A VP, or PR A
responses to hemorrhage (Figure 4-5 and 4-6), it did alter the PaC02 and pHa responses
(Figure 4-3). The greater increases in PaC02 and decreases in pHa in the vagotomized group
may reflect a greater decrease in fetal cardiac output and a concomitant greater decrease in
fetal umbilical-placental flow in the vagotomized fetuses.
Vagotomy also altered the CVP responses to the hemorrhage (Figure 4-2). Intact
fetuses defended CVP well during this hemorrhage while vagotomized fetuses responded to
the hemorrhage with a substantial decrease in CVP. The maintenance of CVP in the intact
fetuses may have been dependent on rapid restitution of blood volume. Because fetal sheep
do not release red blood cells into the circulation after acute sympathetic stimulation (Brace,
1983), changes in hematocrit can be used to follow acute changes in blood volume. Assuming
the fetal body weight was approximately 3.3 kg (calculated from the relation of gestational
age to fetal body weight) as described by Robillard and Weitzman (Robillard and Weitzman,
1980) and assuming that fetal blood volume is 110 ml/kg (Brace, 1983), we can estimate that
approximately 33 ml (28% of the volume removed between the 0- and 120-minute samples)
of fluid re-entered the fetal vascular space during the fetal hemorrhage. Using a similar
approach, we can calculate that only 20 ml (17% of the volume removed ) of fluid re-entered


43
the fetal vascular space in the vagotomized fetuses. This apparent difference in the rate of
volume restitution may have been the cause of the greater decrease in CVP in the vagotomized
fetuses. It is also possible that vascular compliance was lower in the vagotomized fetuses. In
any event, the reduced rate of volume restitution and/or decreased vascular compliance may
have contributed to an impairment of cardiac output and umbilical-placental blood flow,
which, in turn, produced the greater increase in PaCG2 and decrease in pHa.
The difference in initial hematocrit in the intact and vagotomized groups may have
also reflected alteration of fetal fluid balance by vagotomy. It is tempting to propose that the
vagotomy produced an expanded plasma volume and, therefore, secondarily, a decrease in
hematocrit by dilution of the red blood cells. This remains to be tested.
In summary, we have found that vagotomy altered the blood gas and CVP responses
to slow hemorrhage in the sheep fetus but did not alter the magnitudes of the ACTH, AVP,
or renin responses. The results suggest that the control of these hormonal responses to
hemorrhage in the fetus is fundamentally different from that in the adult. The data suggest
the possibility that hormonal responses to hemorrhage in the fetus are stimulated by
chemoreceptor activity, secondary to the acidemia or hypercapnia of fetal hemorrhage.


CHAPTER 5
ACTH, A VP, AND RENIN RESPONSE TO INTRAVENOUS INFUSION
OF HYDROCHLORIC ACID ARE CHEMORECEPTORS RESPONSIBLE
FOR FETAL HORMONE SECRETION?
5.1 Introduction2
The secretion of ACTH, AVP, and renin are stimulated by hemorrhage, hypotension,
and hypoxia. In adult animals, the responses of these hormone systems to hemorrhage and
hypotension are mediated by arterial and atrial mechanoreceptors (Brennan et al., 1971; Bunag
et al., 1966; Cryer and Gann, 1973; Gann et al., 1964; Redgate, 1968; Share and Levy, 1962)
and, for renin, by the intrarenal baroreceptor and the macula densa (Davis and Freman, 1976).
Because resting mean arterial pressure is much lower in the fetus than in the adult, it is not
clear that similar mechanisms govern the ACTH, AVP, and PRA responses to hemorrhage and
hypotension in fetal sheep.
These endocrine systems were investigated in previous experiments to show their
responses to vena caval obstruction (Wood, 1989a, Wood et al, 1982) and to slow hemorrhage
(Chapter 4). Vena caval obstruction, a stimulus that produces a large and rapid decrease in
fetal arterial pressure increased fetal ACTH, AVP, and PRA to levels that were related to the
induced change in arterial blood pressure. Heart rate was decreased to levels significantly
related to the induced change in arterial blood pressure. Sino-aortic denervation attenuated
the ACTH, AVP, and heart rate responses, suggesting that the afferent pathways for these
reflexes were interrupted by removal of either the mechanoreceptor or the chemoreceptor
This work was in part supported by the National Heart, Lung, and Blood Institute
grant HL-36289.
44


45
afferent fibers from the carotid sinuses or aortic arch (Wood, 1989a). The attenuation of the
bradycardia normally observed during fetal hypotension suggested that these reflex responses
may be mediated by chemoreceptor afferents rather than the mechanoreceptor afferents.
Slow fetal hemorrhage, a stimulus that produces small and prolonged decreases in fetal
arterial pressure, increased fetal PaC02, and decreased fetal pHa; the changes in pHa and
PaCo2 were probably secondary to reduced perfusion of the umbilical-placental circulation
(Faber et al., 1973). The fetal ACTH, A VP, and renin responses to the hemorrhage were
highly correlated to the change in pHa but were not correlated to the induced change in fetal
mean arterial or central venous pressure. We performed these experiments to test the
hypothesis that the acute acidemia, in the absence of hypovolemia, stimulates fetal ACTH,
AVP, and renin secretion.
5.2 Methods
Eight chronically catheterized pregnant ewes and their fetuses were studied. Two of
these ewes carried twins; the other six carried singleton fetuses. On the days that the fetuses
were studied, the ages ranged from 132 to 140 days gestation.
Hydrochloric acid (HC1) was infused into the fetal inferior vena cava at one of three
different rates (0.02, 0.10, or 0.50 meq/min) for 60 minutes. All infusions were performed
using a constant infusion pump (Sage Instruments model 341 A, Cambridge, MA) at a volume
rate of 0.5 ml/min, with HC1 concentrations in the infsate adjusted to 0.04, 0.5, and 1.0
meq/ml. We performed five infusions of 0.02 meq/min, six infusions of 0.10 meq/min, and
five infusions of 0.50/meq/min. Blood samples (5 ml/each) were drawn from a fetal femoral
arterial catheter at the beginning of the infusion and thereafter at 10-min intervals throughout
the infusion period. As each fetal blood sample was drawn, an additional blood sample (1 ml)
was drawn into a heparinized syringe for measurement of fetal hematocrit and blood gases.
Therefore a total of 42 ml was drawn from the fetal circulation during these experiments.


46
5.3 Results
Intravenous infusion of HC1 at a rate of 0.5 meq/min significantly decreased fetal PHa
and increased PaC02 (Figure 5-1). Results of two-way ANOVAs are reported in Table 5-1.
Paoz was significantly increased over all groups, but this increase was not significantly related
to the rate of infusion. Infusion of HC1 at a rate of 0.02 meq/min did not significantly alter
fetal blood gases; however, infusions of 0.1 and 0.5 meq/min significantly decreased pHaand
increased PaCQ2 beginning 20 and 10 min after the onset of infusion, respectively.
Infusion of HC1 did not significantly alter fetal arterial blood pressure at any of the
rates tested (Figure 5-2, Table 5-1). Fetal heart rate was increased during infusion of 0.5
meq/min but not during infusion of 0.02 or 0.10 meq/min. Fetal heart rate was significantly
increased over the initial level 54-61 min after the onset of infusion in the 0.5 meq/min
group. Initial values of fetal blood pressure, and blood gases were not different among
groups.
Fetal plasma ACTH and AYP were stimulated by infusion of HC1 at a rate of 0.5
meq/min (Figure 5-3, Table 5-1). Fetal plasma cortisol concentration appeared to increase
in all groups (Table 5-1 and 5-2). A posteriori comparison of individual means by Duncans
multiple range test indicated that in the 0.5 meq/min group, ACTH and AVP were
significantly increased (relative to 0 min) at 30, 40, 50 and 60 min and that cortisol was
significantly increased at 50 and 60 min (Table 5-2). Initial values of plasma ACTH and AVP
concentrations were not different among groups). In Figure 5-4 we present the relationships
between fetal arterial H+ concentrations, PaC02 and the plasma concentrations of ACTH and
AVP in the 0.5 meq/min group. Figure 5-4 shows that both hormones are increased at H+
concentrations > 60 nM and PaC02 > 50 mm Hg. Because of the consistent relationship
between blood H+ and ACTH and AVP, there were significant correlations between pHa and
the logarithm of plasma ACTH (r=0.843, n=35) and AVP (r=0.773, n=28). The logarithms of


47
X
CL
en
X
E
JE
CN
O
O
Cl
7.500
A
7.400
7.300
7.200
7.100
7.000
en
X
E
E
CN
O
CL
25-i
23
21
19
17
I I I I I I |
0 10 20 30 40 50 60
Time (minutes)
Figure 5-1. Mean fetal pHa (A), PaCQ2 (B), and PaQ2 (C) during intravenous infusion
of HC1 at rates of 0.02 (filled circles), 0.10 (filled squares), and 0.50 (filled triangles)
meq/min.


43
Table 5-1. Results of ANOVAs
Variable
F (df)
Do*
Time
Dose x time
pH
42.99* (2,13)
118.56* (6,78)
69.61* (12,78)
Paco,
8.00* (2,13)
36.04* (6,78)
12.65* (12.78)
Pao,
0.13 (2,13)
5.40* (6,78)
1.78 (12.78)
Hct
1.48 (2,13)
6.81* (6,78)
1.32 (12.78)
Mean arterial
0.87 (2,13)
1.35 (60,780)
1.00 (120.780)
pressure
Heart rate
0.12 (2,13)
3.95* (60,720)
1.63* (120,720)
ACTH
4.53* (2,13)
9.86* (6,78)
5.70* (12.78)
Cortisol
0.46 (2,12)
5.50* (6.72)
1.87 (12.72)
AVP
2.33 (2,10)
2.87* (6,60)
3,65* (12.60)
PRA
2.82 (2,13)
3.81* (6,78)
1.12 (12,78)
Paco, and Pao,, arterial partial pressure of C07 and 0:. respectively;
Hct, hematocrit; AVP, arginine vasopressin; PRA, plasma renin activ
ity; ANOVA, analysis of variance; df, degrees of freedom. P < 0.05.


Arterial Pressure (nnm Hg)
49
c
o
I
2
l 1 1 1 1 1 1 I I I I 1 1 1
o 10 20 yj 40 50 60 0 10 20 30 40 50 60
|200
-180
-160
-140
r200
-180
-160
1140
r200
-180
-160
-140
Time (minutes)
Figure 5-2. Fetal MAP (left) and HR (right) during intravenous infusion of HC1 at
rates of 0.02 (bottom), 0.10 (middle), and 0.50 (top) meq/min.
Heort Rate (bpm)


PRA AVP ACTH
(ng Al/ml/hr) (pg/ml) (pg/ml)
50
Time (minutes)
Figure 5-3. Mean fetal plasma ACTH (A), AVP (B), and PRA (C) during intravenous
infusion of HC1 at rates of 0.02 (filled circles), 0.10 (filled squares), and 0.50 (filled
triangles) meq/min.


Table 5-2. Fetal plasma cortisol concentrations
Time,
rain
Infusion Hale, mcq/inin
0.02
0.10
w.ro
0
2G8
232
19 5
10
2G 10
224
204
20
236
204
195
30
29G
224
25 6
40
35 11*
246t
27G
50
317
224t
3l6*t
GO
33 9
194
337*t
Values are means SE. Significantly different from initial time
point in that group, t Significuntly different from same time point in
0.02-meq/min group. $ Significantly different from same time point in
0.1-meq/min group.


Heart Rate (bpm) AVP (pg/ml) ACTH (pg/ml)
52
r
1000
-00
6UU
400
200
0
o
PaC02 (mm Hg)
Figure 5-4. Relationships between arterial H+ concentration (left), PaC02 (right) and
plasma ACTH (top), AVP (middle), and HR (bottom) in 0.50 meq/min group. All
points within the 0.50 meq/min group are shown.
ACTH (pg/ml) AVP (pg/ml) Heart Rate (bpm)


53
fetal plasma ACTH (r=0.742, n=35) and AVP (r=0.754, n=28) were also significantly
correlated to the changes in PaC02. As shown in Figure 5-4, the relationships between heart
rate and pHa and PaC02 were much less consistent. This may be related to the inherent
variability in fetal heart rate.
Fetal PRA was not stimulated by H+ (Figure 5-3, Table 5-1). It is likely that PRA
increased equally in all groups in response to the blood sampling. The logarithm of fetal PRA
was not correlated significantly to the induced changes in pHa (r=-0.007, n=35) or PaC02 (r=-
0.238, n=35) during infusion of 0.5 meq/min. Initial values of PRA were not different among
groups (1-way ANOVA).
Fetal hematocrit was also significantly altered by the infusions, although the effect
was small (Table 5-3). A posteriori comparison of individual means using Duncans multiple
range test indicates a small but significant increase in hematocrit in the 0.02 meq/min group
at 50 min relative to the initial value in that group (mean change in hematocrit=-2%) and a
significant increase in hematocrit at 30 min in the 0.5 meq/min group at 30 min relative to
the initial value in that group (mean change in hematocrit=+l%). The hematocrit values were
significantly lower in the 0.02 meq/min group at all time points compared with the other two
groups.
5.4 Discussion
The results of this study demonstrate that fetal ACTH and AVP secretion are
stimulated by fetal metabolic acidemia in fetal sheep between 132 and 140 days gestation. In
a previous study, we found that ACTH, AVP, and renin responses to slow hemorrhage were
significantly correlated to decreases in pHa and increases in PaC02 in fetal sheep between 128
and 132 days gestation (Chapter 4). The results of these two studies cannot be directly
compared because of the differences in gestational ages of the fetuses. However the results


Table 5-3. Fetal hematocrit
Time,
min
Infusion Kate, meq/min
0.02
0.10
0.50
0
381*
412
411
10
38 1*
412
40 1
20
38 1*
412
41 0
30
38r
402
42 11
40
37 1*
402
4 0 1
50
362*t
402
400
60
37 1*
402
400
Values are means SE. Significantly different from same time
point in other groups, t Significantly different from initial value in
that group.


55
of the present study suggest that fetal ACTH and AVP responses to fetal hemorrhage might
be at least partially mediated by increases in fetal PaC02 or decreases in pHa.
In adult animals, acute metabolic acidemia (produced by intravenous or intraduodenal
infusion of H+) increases plasma concentrations of both glucocorticoid and mineralocorticoids
(Augustinsson and Johansson, 1986; Perez et al., 1979). Chronic metabolic acidosis, produced
by diabetic ketoacidosis, is also associated with increased plasma concentrations of cortisol,
aldosterone, AVP, and renin (Christlieb, 1976; Christlieb et al., 1975; Gerich et al., 1971;
Walsh et al., 1979). However, the hormonal responses to diabetic ketoacidosis may be in part
related to the associated hypovolemia (Waldhausl et al., 1979).
In fetal animals, acute acidemia is known to increase plasma concentrations of AVP
and epinephrine (Faucher et al., 1987). In that study, the investigators infused NH4C1 into
fetal sheep at 137+4 (SD) days gestation at a rate of 0.382 meq/min for 120 min. That rate
of acid infusion decreased fetal pHa from 7.37+0.01 to 7.04+0.05 at the end of the 120-min
infusion but did not alter fetal Pa02 and PaC02. The acidemia stimulated an increase in fetal
plasma AVP from 2.85 + 0.23 to 5.26 + 1.1 ljiU/ml during the 120-min infusion period. In
the present study, the infusion of HC1 at a rate of 0.5 meq/min for 60 min. The rate of HC1
infusion increased PaC02, as well as decreasing pHa, and increased plasma AVP. We found
that this infusion of HC1 increased plasma AVP from 1.1+0.3 to 7.0+3.0 pg/ml, a nearly seven
fold increase. While it is not valid to compare absolute values for plasma AVP between
laboratories, it is apparent that Faucher and co-workers (Faucher et al., 1987) observed only
an approximately twofold increase in plasma AVP during their acid infusion study. The
major difference between our study and theirs is that our infusion of HC1 increased PaC02,
while their infusion of NH4C1 did not. This was probably related to the higher rate of
infusion and the stronger acid used in our experiments. Together, these studies may indicate
that there is a significant interaction between acidemia and hypercapnia in the control of AVP
secretion in the fetus. Whether this apparent effect of hypercapnia is mediated by the


56
peripheral or central chemoreceptors is not known. Another difference between these studies
is the rate of change of pHa. In the present study, pHa decreased at an apparently linear rate
of 0.36 pH units/h, and in the Faucher study pHa decreased at an apparently linear rate of
0.17 pHa units/h. The possible influence of the rate of change of pHa on A VP secretion is
unknown at the present time.
Fetal heart rate was increased by infusion of HC1 at a rate of 0.5 meq/min.
Stimulation of peripheral fetal chemoreceptors by fetal intravenous cyanide injection or
occlusion of the maternal descending aorta produces reflex bradycardia (Iskovitz and
Rudolph, 1982). Analogously, chemoreceptor stimulation in adult animals produces
bradycardia if ventilation is maintained constant(i.e., if the reflex tachypnea is blocked). If
reflex tachypnea is allowed in adult animals after stimulation of the chemoreceptors, one
observes tachycardia, indicating an interaction between the chemoreceptor and pulmonary
afferent fibers in the control of heart rate. It is possible that in the present experiments the
fetal sheep developed tachycardia during HC1 infusion of 0.5 meq/min because they also
started fetal breathing movements. We did not measure fetal breathing movement in this
study; however, it is known from other studies that hypercapnia stimulates fetal breathing
movement (Walker, 1984b). In summary, it is therefore possible that infusion of HC1 at a rate
of 0.5 meq/min stimulated increases in fetal heart rate because of increased stimulation of
chemoreceptors combined with stimulation of fetal breathing movement. Fetal heart rate
during acid infusion was also measured in a study by Widness and co-workers (1986). In that
study, infusion of lactic acid at a rate of 0.58-0.75 meq/min decreased fetal arterial pH from
7.37 to 7.21 over the course of 4.5 hour. The rate of change of pHa was lower (0.04 pH
units/h) than in the present study. There were no significant changes in fetal heart rate or
Paco2- I* is possible that the changes in heart rate and PaC02 in the present study were
partially dependent on the rate of change of pHa.


57
Infusion of acid into the fetal circulation increased fetal PaC02. In adult animals with
spontaneous ventilation, arterial acidemia reflexly increases ventilation, decreasing PaC02.
The fetal animal controls gas exchange by altering umbilical-placental blood flow. In the
present experiments, it is apparent that the PaC02 increased because umbilical-placental blood
flow did not increase accordingly.
We conclude that acute acidemia is a potent stimulus to ACTH and AVP secretion in
fetal sheep between 132 and 140 days gestation. The lack of response of PR A to the acidemia
may indicate insensitivity of renin to control by changes in pHa or PaC02 or may have been
the result of secondary inhibition of renin secretion by the increased CP load at the fetal
macula densa (Share and Levy, 1962). These results support the hypothesis that the acidemia
produced during hemorrhage might partially stimulate the ACTH and AVP responses to the
hemorrhage.


CHAPTER 6
REFLEX CONTROL OF FETAL ARTERIAL PRESSURE
AND HORMONAL RESPONSES TO SLOW HEMORRHAGE
6.1 Introduction3
Fetal sheep respond to slow hemorrhage with increases in fetal plasma ACTH and
AVP concentrations and PRA (Alexander et al., 1974; Brace and Cheung, 1986; Drummond
et al., 1980; Ross et al., 1986). From Experiment I (Chapter 4), we found that bilateral
vagotomy, which interrupts afferent fibers from atrial type B receptors did not alter the
ACTH, AVP or PRA responses to hemorrhage. The receptors mediating the hormonal
responses to mildly hypotensive hemorrhage are therefore different in the fetus than in the
adult (Cryer and Gann, 1974; Share and Levy, 1962). We and others have demonstrated that
the ACTH, AVP, and renin responses to hemorrhage were significantly correlated to changes
in pHa, but were not correlated to changes in arterial or venous pressure. From Experiment
II, we found that hypercapnic acidemia, produced by infusion of hydrochloric acid increased
fetal ACTH and AVP (Chapter 5). Together, the results of these studies suggest that ACTH
and AVP responses to slow hemorrhage might be chemoreceptor-mediated.
The present study was designed to investigate the role of peripheral chemoreceptors
in controlling the fetal hormone secretion during slow hemorrhage. To test this hypothesis,
we compared responses to slow hemorrhage in intact fetuses to responses in fetuses subjected
to bilateral vagotomy combined with bilateral carotid sinus denervation. The combined
3 This work was supported by the National Institute of Health grant HD-20098.
58


59
denervation impaired the ability of the fetus to defend blood pressure during the period of
hypovolemia, exaggerating the changes in fetal arterial blood gases usually produced by
hemorrhage. We therefore added a third group, denervation plus infusion of phenylephrine
(an a-adrenergic agonist drug) to support blood pressure and umbilical-placental perfusion
during the period of hypovolemia. Comparison of these three experimental groups allows
assessment of the roles of carotid sinus and vagal afferents together in the control of reflex
hormonal and hemodynamic responses to slow hemorrhage in the late-gestation fetal sheep.
6.2 Methods
6.2.1 Experimental Protocol
Twenty-six chronically catheterized fetal sheep of 121-138 days of gestation were
studied. Four of them were twins. Nineteen of these fetuses were subjected to bilateral
section of cervical vagosympathetic trunks and the carotid sinus nerves in order to deafferent
peripheral chemoreceptors and baroreceptors.
All fetuses underwent the same 120-minute hemorrhage procedure, and each fetus was
studied once. At ten-minute intervals, 11 ml blood was withdrawn from a fetal arterial
catheter. One ml of the blood was drawn anaerobically for analysis of fetal pHa, Pa02, PaC02,
plasma protein, plasma sodium, potassium and Hct and 10 ml were used for hormone analysis.
Therefore, the total volume of blood withdrawn was 143 ml. One maternal arterial blood
sample was withdrawn at the beginning of each experiment. Each fetus was studied once.
The fetuses were divided into three groups: 1) intact fetuses (n=7); 2) denervated
fetuses (n=12); 3) denervated fetuses infused intravenously with phenylephrine hydrochloride
(Winthrop-Breon Laboratories, Division of Sterling Drug, Inc.) using a syringe pump (Sage
Instruments model 341, Cambridge, MA). The rate of phenylephrine infusion was adjusted
to maintain the fetal blood gases at pre-hemorrhage levels. Infusion was started during the


60
period between 30 to 40 minutes after the onset of the hemorrhage; the rate of infusion was
varied between 0.01 ml/min and 0.38 ml/min (0.2-7.6 /g/ml). All ewes and fetuses were
sacrificed and the fetuses were weighed immediately after the experiments.
6.2.2 Calculated Variables
All of the following calculations were performed as described by Brace and coworkers
(Brace and Cheung, 1986; Brace, 1983).
Initial blood volume (BV0) was assumed to be approximately 110 ml/kg, and
subsequent blood volume at each time point (BVt) was calculated from BV0, Hct of each
sample (Hctt), and volume of blood removed from the fetus as measured by Brace (Brace and
Cheung, 1986). Therefore,
BV0 = 110 ml/kg x Wt [1]
and
BVt = BV0 x FRCV x Hct0/Hctt [2]
where Hct0 and Hctt are initial and subsequent hematocrits, respectively, and FRCV is the
fractional red cell mass. In this study, FRCV was calculated as follows:
First, calculate the initial red blood cell mass (RBC0):
RBC0 = BV0 x Hcto/100
Then, subsequent RBC remaining (RBCt) at each 10-min interval of hemorrhage was
calculated as:


RBCt = Initial RBC RBC removed during hemorrhage
= RBC0 11 x (Hct0 + Hctx +...+ Hctt)/100
61
Thus,
FRCV = RBCt / RBC0
Vr and Rf are referred to as the blood volume removed and the blood volume
restitution during hemorrhage. We have
Vr = 11 x n
and
Rf= Vr-(BV0-BVt)
where n is the number of 11 ml samples. Therefore, the %R after hemorrhage was calculated
using the following equations (Brace, 1983):
%R = Rf/Vr x 100 [3]
Assuming that the fluid entering the circulation contained no protein, the percent
change of the calculated or theoretical plasma protein concentration (%aPc) was calculated
(Brace, 1983) by
%aPc = 100 x (Hct0 Hctt)/(100 Hct0) [4]
The %APa was calculated by
%APa = (P0 Pt)/P0 x 100
[5]


62
where P0 is the plasma protein concentration before hemorrhage and Pt is the protein
concentration at each time point.
The protein concentration in restitution fluid (Prf) was calculated by
Prf = (Pt Pc) x BVt/Rf [6]
where
Pc = (1 + 0/0APc) x p0
6.3 Results
Initial values of all fetal blood gases, blood pressures, HR and fetal and maternal
hormone concentrations were similar to values previously reported for healthy fetuses and
ewes in this laboratory (See previous chapters), suggesting that the fetuses had recovered from
surgery. Initial values of variables were not significantly different among experimental
groups as tested by one-way ANOVA.
Maternal plasma ACTH concentrations in intact, denervated, and denervated plus
phenylephrine infusion groups were 103+40, 167+39, and 120+41 pg/ml, respectively, and
maternal plasma cortisol concentrations in these groups were 11.7+2.5, 13.3+2.1, and 9.6+1.5
ng/ml, respectively. Maternal plasma vasopressin concentrations in the three groups were
0.8+0.2, 4.3+1.2, and 3.4+1.2 pg/ml, and plasma renin activities were 2.7+1.1, 1.7+0.2, and
2.0+0.8 ng Ang I/mlhr, respectively. None of the measured maternal plasma hormone levels
differed significantly among groups, as tested by one-way ANOVA.
6.3.1 Changes in Hemodynamic Variables During Hemorrhage
Hemorrhage decreased fetal MAP in both intact (Group 1) and denervated (Group 2)
fetuses. The decrease in MAP was more severe in the denervated fetuses (Figure 6-1, top


63
Figure 6-1. MAP (top), HR (middle) and CVP (bottom) during hemorrhage in fetal
sheep which were intact (left), subjected to bilateral sino-aortic and vagosympathetic
denervation (middle), and subjected to denervation plus phenylephrine infusion
(right).


64
panel). Infusion of phenylephrine increased arterial blood pressure during hemorrhage in
denervated fetuses (Group 3).
Heart rate increased in all groups during hemorrhage (Figure 6-1, middle panel).
There were no significant differences among groups. Fetal CVP was significantly decreased
during hemorrhage in intact fetuses (Figure 6-1, bottom panel).
6.3.2 Changes in Blood Gases During Hemorrhage
The initial values of PaC02 and pHa were not significantly different. Hemorrhage
significantly decreased fetal pHa and increased PaC02. The changes of pHa and PaC02
produced by the hemorrhage were greatly exaggerated by denervation; infusion of
phenylephrine restored the pHa response to a magnitude that was not different from that in
intact fetuses. PaG2 was not significantly altered by the hemorrhage (Figure 6-2, top panel).
6.3.3 Changes in Plasma Hormone Levels
Hemorrhage stimulated fetal ACTH and cortisol secretion in all three groups compared
to either intact or denervated fetuses infused with phenylephrine (Figure 6-3, left panel).
The responses were greatest in denervated (Group 2) fetuses. Infusion of phenylephrine
attenuated these responses such that the magnitudes of the responses were similar to those of
the intact fetuses. Plasma ACTH concentration was significantly higher than the other two
groups after 70 min in denervated fetuses. Plasma ACTH concentration in Group 3
(denervated plus infusion of phenylephrine) was lower than the concentration in Group 1
(intact) at 120 min. Plasma cortisol concentration was higher in denervated fetuses after 20
min than in either of the other two groups. There were no significant increases in cortisol
above initial concentrations in either group 1 or group 3.
Hemorrhage stimulated fetal A VP secretion in both intact and denervated fetuses.
Phenylephrine infusion abolished the A VP response to hemorrhage in denervated fetuses


65
7.430-r
7.380-
7.330-
7.280-
7.230-
7.180-*-
65
60
55
50
45
40
35
PaC02 (mm Hg)
i MU'* l
3
1
-tIIIIIIIIIIIII
0 40 80 120
Time (min from onset of hemorrhage)
Figure 6-2. Pa02, pHa and PaC02 during hemorrhage in fetal sheep which were intact
(filled circles), denervated (filled triangles) and denervated plus phenylephrine
infusion (filled squares).


66
3000
Fetal Plasma ACTH (pg/ml)
50
40
30
20
10
0
Fetal Plasma AVP
(pg/ml)
A
Time (min from onset of hemorrhage)
Figure 6-3. Fetal plasma ACTH (top left), cortisol (bottom left), AVP (top right) and
PRA (bottom right) during hemorrhage in fetal sheep which were intact (filled
circles), denervated (filled triangles) and denervated plus phenylephrine infusion.


67
(Figure 6-3, right top panel). There was a significant suppression of AVP in the denervated
fetuses infused with phenylephrine after 110 min relative to the denervated fetuses not
infused with phenylephrine.
Hemorrhage stimulated similar PRA responses in all 3 groups (Figure 6-3, right
bottom panel).
6.3.4 Blood Volume Restitution
All fetuses were bled the same absolute volume of blood. The ratio of hemorrhage
volume to estimated initial blood volume was not different among groups: 47.0 0.1%,
47.0 0.1%and53.7 0.1% for Groups 1,2, and 3, respectively. Figure 6-4 shows that intact
fetuses restored blood volume better than the fetuses in the two denervation groups. The
effect of the denervation on blood volume restitution is summarized in Table 6-1.
Denervation reduced the final restitution of blood volume 21.2% (calculated from volumes
expressed as ml/kg) or 23.4% (calculated from volumes expressed as the percentage of
hemorrhage volume). Infusion of phenylephrine did not restore the rate of blood volume
restitution observed in the intact fetuses.
Plasma protein concentrations decreased in all three groups, (Figure 6-5, left bottom).
The decrease in plasma protein concentration suggests that transcapillary refilling occurred
with fluid containing protein at a concentration less than that of plasma. Figure 6-6 illustrates
the percentage change in plasma protein that was measured and the calculated change
assuming there is no protein in the fluid entering the vascular space. The values were
significantly different between measured and calculated values within each group. This
analysis can be used to calculate the mean protein concentration in the fluid entering the
vascular space. These values are reported in Table 6.1. The protein concentrations range
from 2.7 0.4 to 3.7 0.2 g/dl, and are not significantly different among groups.


68
Time (min from onset of hemorrhage)
Figure 6-4. Fetal volume restitution, which is represented as ml/kg (top) and
percentage changes of hemorrhage volume (bottom). Filled circles, triangles and
squares are represented intact, denervated and denervated plus phenylephrine infusion
groups.


69
Table 6-1. Initial and final fetal blood volume and fetal blood volume restitution.
INTACT DEN@ DEN+PHE
INITIAL BV (ml)
(estimated)
FINAL BV (ml)
(estimated)
FINAL HEMORRHAGE
RATIO (% of BV0)
FINAL BV
RESTITUTION (ml/kg)
FINAL BV
RESTITUTION
(% of hem. volume)
309.0
211.0
47.0
16.5
31.5
15.0
14.0
+ 0.1
1.9
+ 2.6
319.0
213.0
47.0
#13.0
25.4
+ 22.0
22.0
0.1
L2
+ 2.2
273.0
156.0
53.7
#*10.7
#*18.3
17.0
18.0
0.1
1.3
+ 2.4
FINAL PROTEIN CONC. 3.7 + 0.2
IN RESTITUTION FLUID (g/dl)
3.5 + 0.6 2.7 + 0.4
# Duncans multiple test shows significant difference from intact fetuses.
* One-way ANOVA shows significant difference among groups.
@ DEN: denervated fetuses; DEN + Phe: denervated plus phenylephrine infusion


70
+.300
+.100
3.900
3.700
Plasma Potassium (mEq/L)
s
h
s
tH-
rTTf
]y
S
+
-
1
1
2
3.500
Figure 6-5. Fetal Hct (top left), plasma protein (bottom left), potassium (top right)
and sodium (bottom right) in fetuses which were intact, denervated and denervated
plus phenylephrine infusion (filled circles, triangles and squares, respectively).


71
10T % Protein Concentration
-10
-20
-30
10
'O...
? a. T
o
GROUP I
(n=7)
1Xt t
T
o
1
0-- A-
-10-
-20-
-30-
10T
. ,
^ i i,. *-*-*
* A.
'A- r
* 'A.
*A*A.
GROUP 2
(n=1l)
-10
-20
***"-
GROUP 3
1 - T I
i y- --Q.
* i -v
T

1
(n = 7)
-30-1 1 1 1 1 1 1 1 t-i 1 1 1 1 1
0 40 80 120
Time (min from onset of hemorrhage)
Figure 6-6. Percent changes in fetal plasma protein concentration. Open symbols
represent the theoretical changes and the filled symbols represent the actual changes.


72
Plasma potassium and sodium concentrations were only measured in 7 intact (Group
1) and 11 denervated (Group 2) fetuses (Figure 6-5, right). There was a tendency for plasma
potassium concentration to decrease during hemorrhage, but the apparent changes were not
statistically significant. There were also no significant differences in plasma sodium
concentrations between groups.
6.4 Discussion
This study was designed to test the role of peripheral chemoreceptors and cardio
vascular mechanoreceptors in the control of the hormonal and cardiovascular responses to slow
hemorrhage in the late gestation fetal sheep. We found that section of the vagosympathetic
trunks plus bilateral denervation of the carotid arterial baroreceptors and chemoreceptors had
a profound effect on the responses to hemorrhage. We successfully controlled the exaggerated
changes in blood gases during hemorrhage by infusing phenylephrine (an a-adrenoreceptor
agonist) into the denervated fetuses during hemorrhage to constrict the fetal systemic
vasculature, and to increase placental flow to maintain changes in fetal arterial blood gases
that were similar to those observed in the intact fetuses. The infusion of phenylephrine did
not, however, improve BV restitution in denervated fetuses. The phenylephrine infusion
attenuated the ACTH and cortisol responses and blocked the AVP response, but did not
change the PRA response.
6.4.1 Alterations in Blood Gases and Vascular Pressures
The greater decreases in MAP and pHa and the greater increase in PaCQ2 suggested
that the afferent fibers sectioned in the denervated compared to intact fetuses are important
in the reflex vasomotor responses to hemorrhage. In a previous study, we compared responses
to hemorrhage in intact and vagotomized only fetuses and the later were not significantly


73
different from the responses in intact fetuses. Therefore, it is likely that afferent fibers from
the carotid sinus are critical for maintaining arterial pressure and blood gases during
hemorrhage. It is also possible that interruption of fibers important for maintenance of
arterial blood pressure during hypovolemia requires both vagotomy and carotid sinus
denervation, since we did not test the response to hemorrhage in fetuses subjected to carotid
sinus denervation alone.
The large changes in fetal arterial blood gases in the denervated fetuses not infused
with phenylephrine was most probably the result of reduced flow in the umbilical-placental
vascular bed secondary to reduced arterial blood pressure. Umbilical-placental flow is
influenced by the relative distribution of fetal combined ventricular output between the
umbilical-placental vascular bed and other vascular beds in the fetus (Itskovitz et al., 1982;
Faber etal., 1973; Perez et al., 1989). Reflex control of blood pressure and blood gases during
hemorrhage involves vasoconstriction in the fetal body and redistribution of combined
ventricular output to the placenta. The results of these and other experiments demonstrate
that the umbilical-placental vascular bed is less sensitive to alpha-adrenergic stimulation than
other vascular beds in the fetus (Berman, 1978; Oakes et al., 1980). Thus, infusion of
phenylephrine during hemorrhage in the denervated fetuses redistributes flow to improve gas
exchange.
Central venous pressure did not decrease as much in the totally denervated fetal sheep
as much as in the intact fetal sheep. It is possible that, if the denervation partially blocked
the reflex sympathetic efferent response to the hemorrhage, cardiac contractility would not
have been as high in the denervated fetuses as in the intact fetuses. We therefore speculate
that central venous pressure does not fall during hemorrhage in the totally denervated fetuses
because of a reduced of cardiac output compared to the intact fetuses.


74
6.4.2 Reflex Hormonal Responses
ACTH, A VP, and PRA were increased in the intact fetuses. The magnitudes of the
responses appeared related to the changes in pHa and PaC02, confirming results of previous
studies by us and others (Challis et al, 1989; Faucher et al, 1987; Chapter 4 and 5). However,
none of the responses were inhibited or attenuated by denervation, which suggests that the
sectioned fibers were not the sole mediators of the hormonal responses. In other experiments,
severe hypercapnic acidemia caused by HC1 infusion in intact fetuses (pHa from 7.397+0.008
to 7.038+0.038; PaC02 from 43.1+1.8 to 57.5+3.2 mm Hg) increased both ACTH and A VP
secretion (Chapter 5). Therefore, assuming that the responses to hypotension in the intact
fetus are not mediated by cerebral ischemia, central chemoreceptors might mediate part of
the A VP response to slow hemorrhage. Together, these results prove that severe hypercapnic
acidemia is a stimulus to ACTH and AVP secretion. It is likely that peripheral
chemoreceptors do not mediate either the AVP or the ACTH response to slow hemorrhage.
The role of central chemoreceptors in the regulation of fetal ACTH and AVP secretion
might be greater during hemorrhage than during metabolic acidemia. Central chemoreceptors
might have been greatly stimulated by the combination of the exaggerated increase in PaC02
and a possible reduction in cerebral blood flow in the denervated group caused by
hypotension. The augmented ACTH and the unchanged AVP responses in the denervated
group were either attenuated or inhibited after phenylephrine infusion. It is possible that
phenylephrine removed the remaining stimulus to central chemoreceptors by normalizing the
blood gas responses and increasing cerebral blood flow during the hemorrhage. Alternatively,
it is also possible that cardiac mechanoreceptors with non-vagal afferent fibers contributed
to the ACTH and AVP response to hemorrhage after denervation might reflect the different
sensitivity of each receptor not deafferented by the vagotomy and carotid sinus denervation.
Finally, it is not likely that osmoreceptors stimulated AVP secretion in current study.


75
Although we did not measure plasma osmolality, plasma sodium concentration did not change,
suggesting little change in plasma osmolality.
PRA responses to the hemorrhage were not altered by denervation or by infusion of
phenylephrine in the denervated fetuses. These results do not, by themselves, rule out the
control of renin secretion by peripheral or central chemoreceptors. However, changes in pHa
and PaC02 are not potent stimuli to renin secretion (Wood et al., 1989). We have demonstrated
that, although PRA responses to hypercapnia, isocapnic hypoxia, or hypercapnic hypoxia are
statistically significant, the responses are smaller in magnitude than the responses to
hemorrhage. PRA responses to hypercapnia are attenuated by sinoaortic denervation (Wood
et al., 1989). Together, the results of this and our previous studies suggest that the renin
response to hemorrhage is only partially mediated by peripheral chemoreceptors.
Alternatively, it is possible that PRA responses are also influenced by other factors, such as
humoral substances like atrial natriuretic peptide (Scheuer, 1987), and other cardiovascular
mechanoreceptors that are not identical with the carotid sinus or aortic arch
mechanoreceptors, and do not have afferent fibers in the vagosympathetic trunks.
6.4.3 Defense of Blood Volume
The reduction of fetal hematocrit during hemorrhage reflects the restitution of blood
volume. Since under normal conditions the placenta is quite impermeable to molecules even
as small as sodium (Schroder, 1982), the restitution fluid is thought to come mostly from the
fetal interstitial space (Robillard et al., 1979; Brace, 1983). The calculated protein
concentration in restitution fluid and the lack of change in the plasma sodium and potassium
concentrations in the present study support this notion. However, it is also possible that
during hypovolemia the permeability of the placenta increases, allowing transplacental inflow
of some fluid from the mother to the fetus (Manku et al., 1975). The high protein


76
concentration in restitution fluid is also consistent with increased lymphatic return or
decreased protein leakage from the circulation.
The average volume restitution in the intact group, expressed as the percentage of the
hemorrhage volume, is about 31.5% (ranged from 28.9% to 34.1%). These values are less than
those calculated in Braces studies, approximately 50% (Brace and Cheung, 1986; Brace, 1989).
This might be related to the shorter observation period in the present experiments, and related
to the probable underestimation of fetal body weight before hemorrhage.
In conclusion, the results of the present experiment demonstrate that carotid sinus
baroreceptors or chemoreceptors are important for the maintenance of blood pressure and
blood gases during hemorrhage. The results of this and other studies from this laboratory
indicate that PRA responses to slow hemorrhage might be partially mediated by peripheral
chemoreceptors, and that AYP and ACTH responses are not mediated by peripheral
chemoreceptors. Elucidation of the possible role of the central chemoreceptors or other
baroreceptor populations needs further investigation.


CHAPTER 7
THE ACTH AND AVP RESPONSES TO NORMOXIC HYPERCAPNIA
IN FETAL AND MATERNAL SHEEP
7.1 Introduction4
The fetal hypothalamus-pituitary-adrenal axis and neurohypophysis are functional
beginning early in fetal life. The activity of these endocrine axes is increased by various
hemodynamic stimuli, starting at approximately 90 days gestation (Alexander et al., 1972) and
are important for intrauteral survival during fetal stress.
From Experiment I and III (Chapters 4 and 6, respectively), we have demonstrated
that slow hemorrhage stimulates plasma ACTH, cortisol and vasopressin secretion in late
gestation fetal sheep. In Experiment I, bilateral vagotomy showed no effect on hormonal
responses; the hormonal responses were significantly correlated to changes in arterial pHa, but
not to changes in arterial or venous pressure, which suggested that the ACTH and AVP
responses during hemorrhage might be chemoreflex-mediated. In Experiment II, severe
hypercapnic acidemia, produced by intravenous infusion of hydrochloride acid, stimulated
ACTH, cortisol and AVP secretion, suggesting that chemoreceptors might play an important
role in mediating fetal hormonal responses to hemorrhage (Chapter 5). While this assumption
was disproved by Experiment III (Chapter 6): 1) a more complete peripheral
chemodenervation did not attenuate the ACTH, cortisol, AVP and PRA responses to
hemorrhage; 2) when the fetal blood pHa and PaC02 changes during hemorrhage were
4 This work was supported by the National Heart, Lung, and Blood Institute
grant HL-36289 and American Heart Association.
77


78
balanced by infusion of an alpha-agonist, the ACTH, cortisol and A VP increases in
denervated fetuses were either attenuated or inhibited. Results from Experiment Series III
suggests that peripheral chemoreceptors do not mediate ACTH, AVP or PRA responses to
hemorrhage, and a central chemoreceptors was suggested.
This conclusion made us question the assumption we made from Experiment II
(Chapter 5), which is: chemoreceptors might mediate ACTH and AVP responses to
hemorrhage. Based on the facts that HC1 infusion caused metabolic acidemia while slow
hemorrhage caused respiratory acidemia, and the former caused much severe acidemia than
slow hemorrhage did, We speculated that there must be a threshold for initiating
chemoreceptor regulated hormonal responses, and this threshold might not be reached during
slow hemorrhage.
The present study was designed to investigate whether mild hypercapnic acidemia,
similar in magnitude to the changes during hemorrhage but without the associated
hypovolemia, stimulates ACTH and AVP secretion in fetal sheep, and whether these responses
are mediated by peripheral chemoreceptors.
7.2 Methods
Twelve fetal sheep of 123-137 days of gestation were studied. All fetuses and their
mothers were chronically prepared with catheters and six of these fetuses had been subjected
to bilateral section of the cervical vagosympathetic trunks and the carotid sinus nerves in
order to deafferent peripheral chemoreceptors and baroreceptors as well as to remove other
vagal afferent fibers.
The ewes with their fetuses were subjected to two experiments: normocapnia control
and hypercapnia.
A five ml blood samples was withdrawn from both fetal and maternal arterial catheters
every 20 minutes for 1 hour. Immediately after drawing the first fetal and maternal blood


79
samples, a polyethylene bag was fitted over the ewes head and neck, held loosely in place
with elasticized cloth. Normocapnia control was achieved by passing room air through the
bag. Hypercapnia was achieved by using a gas mixture of 21% 02 and between 5% and 8%
COz (adjusted to increase fetal PaCQ2 at least 10 mm Hg). Data from one of the experiments
in each group was eliminated because of the abnormal baseline levels of fetal blood gases or
hormones. The order of the experiments performed was randomized.
CVP was not measured in one of the intact fetuses in normocapnia experiment because
of the failure of the venous catheters.
7.3 Results
Initial values of all fetal and maternal blood gases, hormones and electrolyte
concentrations, fetal blood pressures and HR were similar to values previously reported for
healthy fetuses and ewes in this laboratory, suggesting that the fetuses and ewes had recovered
from surgery.
7.3.1 Responses in Fetuses
During normocapnia, blood gases, Hct and electrolytes did not change significantly
(Table 7-1).
During hypercapnia, pHa decreased from 7.390 0.001 and 7.398 + 0.015 to 7.257 +
0.011 and 7.281 + 0.010, PaC02 increased from 36.8 + 1.4 and 39.8 + 1.4 to 55.2 + 1.8 and 55.9
2.2 mm Hg in intact and denervated fetuses, respectively. Pa02 was increased from 25.5 +
1.4 and 26 + 1.5 to 31.6 + 1.9 and 33.6 + 1.8 mm Hg in intact and denervated fetuses
respectively. Changes in blood gases were not significantly different in intact and denervated
fetuses (Figure 7-1).


HYPERCAPNIA NORMOCAPNIA
80
7.450
7.350
7.250
7.150
7.450
7.350
7.250-
7.150-
phq
T
-I 1 1 1 1
0 20 40 60
TIME (MINUTES)
Figure 7-1. Mean fetal pHa (left), PaC02 (middle), and PaG2 (right) in normocapnia
(upper) and hypercapnia (lower) studies. Open and filled symbols represent intact and
denervated fetuses respectively.


81
Plasma potassium concentration significantly increased during hypercapnia from 3.37
+ 0.07 and 3.42 + 0.11 to 3.62 + 0.10 and 3.63 + 0.19 meq/L in intact and denervated fetuses
respectively (Table 7-1).
There was also a small but significant increase in plasma sodium concentration from
142.3 + 0.8 to 143.7 + 0.7 meq/L in intact fetuses during hypercapnia (Table 7-1).
HR was significantly increased by hypercapnic acidemia only in intact fetuses (Figure
7-2). During normocapnia, there was a significant overall difference in HR between intact
and denervated fetuses, probably reflecting different initial values. CVP was decreased
slightly but significantly after 30 min during normocapnia in the denervated fetuses. CVP
did not change significantly in the other groups. There seems to be some fluctuations of both
MAP and CVP in both intact and denervated fetuses. MAP decreased at 20 and 25 minutes
in denervated fetuses compared to the MAP at 0 minutes, and then returned to normal (Figure
7-2).
There were no significant changes in plasma ACTH concentration in either normoxia
or hypercapnia experiments (Figure 7-3, upper panel). Plasma cortisol concentration was
equally and significantly increased in both intact and denervated fetuses at 40 and 60 minutes
(Figure 7-3, lower panel). The increases in plasma cortisol were equal in the intact and
denervated groups. The plasma concentration of AVP was approximately doubled during
hypercapnia; denervation did not attenuate the AVP response (Figure 7-4).
7.3.2 Responses in Ewes
Hypercapnia significantly decreased maternal pHa from 7.509 + 0.008 to 7.353 + 0.011;
PaC02 increased from 28.4 + 1.1 to 44.2 + 0.9 mm Hg and PaQ2 from 100.2 + 2.6 to 119.9 + 4.2
mm Hg, respectively (Figure 7-5). Plasma potassium concentration also increased during
hypercapnia from 3.99 + 0.10 to 4.27 + 0.10 meq/L (Table 7-2). Plasma sodium concentration
increased slightly during hypercapnia at 20 and 60 minute points compared to the 0 minute


82
Table 7-1. Means & SEs of fetal HCT, plasma potassium & sodium
NORMOCAPNIA HYPERCAPNIA
HCT (% PCV)
INT
DEN
INT
DEN
0
29.1 + 3.1
27.0 + 2.0
27.5 2.1
26.5 + 0.5
20
29.4 3.2
27.2 + 2.0
27.8 2.0
26.3 + 0.6
40
28.8 + 3.2
27.1 + 1.9
27.5 2.1
26.0 3.7
60
30.1 + 3.7
27.1 2.0
27.2 2.0
26.0 0.7
PLASMA POTASSIUM
(meq/L)
0
3.36 0.11
3.72 0.11
3.37 0.07
3.4 0.11
20
3.41 + 0.11
3.68 0.12
3.51 + 0.08
3.4 0.14
40
3.41 +0.12
3.73 + 0.10
3.57 + 0.08*
3.6 .19*
60
3.47 + 0.11
3.77 0.11
3.62 0.10*
3.6 .24*
PLASMA SODIUM
(meq/L)
0
144.0 2.5
144.7 0.9
142.3 0.8
144.7 0.5
20
143.2 1.6
145.0 + 1.1
143.2 + 0.8*
145.5 0.5
40
141.9 0.8
144.3 + 0.8
143.7 0.7*
145.0 0.5
60
141.6 + 0.5
144.3 + 0.7
143.2 + 0.7*
144.6 + 0.4
* Significant difference between the variables of certain time point and
their 0 minute measurements.


HYPERCAPNIA NORMOCAPNIA
83
MAP (mm Hg)
CVP (mm Hg)
220
200-
180-
160
140
120
HR (bp/min)
?9o J
KMWUu
TIME (minutes)
Figure 7-2. MAP (left), CVP (middle) and HR (right) in normocapnia (upper) and
hypercapnia (lower) studies. Open and filled symbols represent intact and denervated
fetuses respectively.


84
E
\
cn
Cl
X
I
o
<
o
E
(0
_D
250
200
150
100
50
NORMOCAPNIA
OO Intact
Denervated
0
HYPERCAPNIA
A A Intact
-A Denervated
Time (minutes)
Figure 7-3. Fetal plasma ACTH (upper) and cortisol (lower) concentration in
normocapnia (right) and hypercapnia (left) studies. Open and filled symbols represent
intact and denervated fetuses respectively.


Plasma AVP (pg/ml)
85
NORMOCAPNIA
O O Intact
Denervated
HYPERCAPNIA
a A Intact
a a Denervated
Time (minutes)
Figure 7-4. Fetal plasma AVP concentration in normocapnia (upper) and hypercapnia
(lower) studies. Open symbols represent intact fetuses, filled symbols represent
denervated fetuses.


7.550
7.450
7.350
7.250
50
45
40
35
30
25
140
130
120
1 10
100
90
Vlatern
>) and
86
Normocapnia (ewes)
Hypercapnia (ewes)
H 1 1 1 1
0 20 40 60
Time (minutes)
-a (upper), PaC02 (middle) and PaQ2 (lower) in normocapnia
ypercapnia (filled squares) experiments.


87
Table 7-2. Maternal means & SEs of HCT, plasma potassium & sodium
NORMOCAPNIA
HYPERCAPNIA
HCT (% PCV)
0
21.8 + 0.7
22.0 0.9
20
21.4 + 0.7
23.8 1.2
* #
40
21.5 0.7
24.3 0.9
* #
60
21.2 + 0.7
23.7 0.9
* #
PLASMA POTASSIUM
(meq/L)
0
3.93 0.05
3.99 0.10
20
3.89 + 0.05
4.17 0.11
* #
40
3.92 + 0.05
4.20 0.11
* #
60
3.89 + 0.06
4.27 + 0.10
* #
PLASMA SODIUM
(meq/L)
0
148.0 0.4
148.8 + 1.6
20
146.5 + 0.8
149.1 + 0.7
* #
40
147.8 0.5
148.8 + 0.5
60
148.0 0.5
149.2 + 0.3
*
# significant difference between groups by Duncans multiple range test.
* Significant difference between the variables of certain time point and
their 0 minute measurements.


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