Vol. 277, Issue 6, R1541-R1552, December 1999
INVITED REVIEW
Central nervous system regulation of reflex
responses to hypotension during fetal
life
Charles E.
Wood and
Haiyan
Tong
Department of Physiology, University of Florida College of
Medicine, Gainesville, Florida 32610-0274
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ABSTRACT |
The ability of the fetus to survive,
grow, and successfully complete the transition from fetal to neonatal
life is critically dependent on the appropriate regulation of fetal
blood pressure, blood volume, and fluid dynamics. This is a short
review of the physiological mechanisms controlling the fetal
cardiovascular system, focusing mainly on the neural and endocrine
elements in the schema of cardiovascular function and control. The
fetal cardiovascular system is arranged anatomically to provide for
perfusion of the umbilical-placental circulation, the organ of gas
exchange of the fetus, and to largely bypass the lungs. Fetal blood
volume and pressure, maintained at levels that are appropriate for this function, are influenced by neural and endocrine control mechanisms, which are similar to, but quantitatively different from, the adult animal. Baroreceptors and chemoreceptors located in the carotid sinuses
and aortic arch sense changes in blood pressure and blood gases and
comprise the afferent limb of the major reflexes that maintain normal
fetal blood pressure and volume. Fetal hypotension stimulates reflex
decreases in fetal heart rate, which are apparently mediated by
chemoreceptor input. Arginine vasopressin responses to hypotension are
most likely mediated by baroreceptor input. Recent evidence suggests
that the reflex responses to hypotension in the fetus are modulated by
paracrine or endocrine factors. For example, baroreceptor or
chemoreceptor reflex pathways are modulated by the endogenous
production of prostanoids and by the preparturient changes in fetal
plasma estrogen concentration.
heart rate; blood pressure; blood volume; development; birth; adrenocorticotropin; vasopressin; renin
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INTRODUCTION |
THE ABILITY OF THE FETUS to survive, grow, and
successfully complete the transition from fetal to neonatal life is
critically dependent on the appropriate regulation of fetal blood
pressure, blood volume, and fluid dynamics. Disturbances in the
development and regulation of fetal cardiovascular function can produce
a variety of problems that increase both mortality and morbidity of the
late-gestation fetus and newborn. This is a short review of the
physiological mechanisms controlling the fetal cardiovascular system,
focusing mainly on the neural and endocrine elements in the schema of
cardiovascular function and control.
Perhaps the best framework on which to base this discussion is the
general principles governing control of blood pressure and volume in
the adult mammal. It is generally accepted that in the adult,
minute-to-minute control of blood pressure is accomplished via neural
afferent control mechanisms (i.e., baroreceptors and chemoreceptors),
and long-term control of blood pressure is accomplished via changes in
vascular volume, compliance, and other variables that are heavily
influenced by endocrine factors (46). This view of cardiovascular
regulation will not be reviewed here, although several points bear
mention. First, control within the adult cardiovascular system is based
on the general principle of negative feedback. Elevated blood pressure
stimulates an increase in the firing rate of arterial baroreceptors,
which activate a reflex response that ultimately reduces heart rate,
cardiac contractility, sympathetic vasoconstrictor tone, and the rate
of secretion of the hormones, which either effect vasoconstriction or
water or electrolyte conservation. Second, the hormonal systems that
influence blood pressure or volume are themselves influenced by neural
receptors on both the high- and low-pressure segments of the
cardiovascular system. Arginine vasopressin (AVP), for example, is
tonically inhibited by both arterial baroreceptors and by atrial
receptors. Nonhypotensive hemorrhage increases the rate of secretion of
AVP in the adult primarily by reducing the afferent firing of the
atrial receptors, and hypotensive hemorrhage increases the rate of AVP
secretion by reducing the firing of both atrial and arterial stretch
receptors (29, 97). Third, the mechanisms controlling ventilation in the adult are integrated with the mechanisms controlling blood pressure. Severe and rapid hemorrhage, for example, might stimulate increases in heart rate by both baroreceptor and chemoreceptor stimulation. These and several other principles will form a basis of
comparison of the fetal and adult control mechanisms. In some respects,
the fetal cardiovascular control systems are similar to those of the
adult. In many respects the control of the fetal cardiovascular system
is different, but rather more appropriate for control of a
cardiovascular system that is optimized for perfusion of the placenta
as the organ of gas exchange.
The fetal cardiovascular system is anatomically arranged in such a way
as to allow blood to bypass the lungs and to provide perfusion of the
placenta (Fig. 1). This is accomplished by
the establishment of several shunts within the fetal cardiovascular system that establish both the lung and the placenta as parallel circuits within a circulation in which both ventricles pump in parallel. The majority of the blood pumped into the pulmonary artery
from the right ventricle passes through the ductus arteriosus rather
than through the lungs. Indeed, only ~8% of the combined ventricular
output perfuses the lungs in the late-gestation fetus. Conversely, a
portion of the blood entering the right atrium passes through the
foramen ovale into the left atrium. The placenta is perfused in
parallel to the other systemic vascular beds. The placenta does not
exhibit much inherent autoregulation of blood flow; therefore, its flow
is affected by the prevailing arterial blood pressure (but sensitively
modified by vasoconstrictors such as ANG II; Refs. 54, 120, 121). For
this reason, regulation of fetal arterial blood pressure is important
for maintenance of efficient gas exchange within the
umbilical-placental circulation.
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Fig. 1.
Schematic representation of course of fetal circulation. LA, left
atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; PA,
pulmonary artery; DA, ductus arteriosus; FO, foramen ovale.
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Not coincidentally, the fetal blood volume (expressed as a proportion
of fetal body weight) is higher, fetal blood pressure is lower, and
fetal heart rate is higher than in the adult. The need for perfusion of
the low-resistance circuit of the umbilical-placental circulation,
combined with the need for fetal sequestration of fluid, which is
essential for fetal growth, dictates a prevailing blood pressure that
is ~50-60% that of the adult. The low blood pressure impairs
the ability of the fetus to defend blood flow to critical organs during
periods of transient hypotension; however, the perfusion of the
placenta and the vasculature of the fetal membranes allows ready access
to large stores of water and electrolyte (in the maternal circulation
and in the amniotic and allantoic fluid), which can be called upon
during fetal hemorrhage (10, 12). In part because of the relatively low
blood pressure, the neural control of the fetal circulation is far more
dependent on chemoreceptor control than is the adult circulation (113). As will be discussed later in this review, this adaptation is a
particular advantage for the fetus, because the major function of the
fetal cardiovascular system is the transport of oxygen and carbon
dioxide from and to the placenta and because changes in gas exchange
can only be effected via changes in placental perfusion. In other
words, the fetus changes its rate of gas exchange by altering fetal
arterial blood pressure and the circulating concentrations of
constrictor hormones, and these changes are heavily dependent on
chemoreceptor input, as is the control of ventilation in the postnatal
animal (27, 115).
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REFLEX RESPONSES TO HYPOTENSION: FETUS VERSUS ADULT |
The reflex responses to hypotension in adult animals and human beings
are classical examples of negative feedback control mechanisms within
cardiovascular physiology. Decreased blood pressure, caused by
hemorrhage, orthostasis, etc., decreases the rate of firing of the
arterial baroreceptors (located in the carotid sinuses and aortic arch;
Ref. 9). The decreased afferent traffic within the carotid sinus nerves
and aortic depressor nerves is transduced into reflex increases and
decreases in sympathetic and parasympathetic efferent activities,
respectively. The resultant increase in heart rate, cardiac
contractility, and vasoconstriction increase cardiac output and
peripheral resistance, returning blood pressure to higher levels (106).
Severe hypotension can reduce arterial blood pressure to a level that
is not sufficient to maintain oxygen delivery to the arterial
chemoreceptors. At these low levels of arterial blood pressure, the
chemoreceptors increase their firing rate (responding to their own,
flow-limited hypoxia), and the resultant reflex response augments the
increase in sympathetic autonomic tone. Extreme hypotension compromises
blood flow to the central nervous system (CNS), triggering the
so-called CNS ischemic pressor response (47). The precise mechanism of
the CNS ischemic pressor response is not known but generally assumed to
be the direct result of tissue hypoxia within the brain. In the adult,
rapid hemorrhage (79) can produce a paradoxical decrease in heart rate.
This reduction in heart rate is caused by the activation of ventricular
C fiber afferents, and is thought to be important for the defense of
cardiac output. During such periods of dramatically reduced venous
return, a reduced heart rate allows increased diastolic filling time.
Although this classical physiological control system is learned by all
beginning students of cardiovascular physiology, the function of the
same system in the fetus is remarkably different.
Fetal blood pressure is regulated at a level that is low (~40 mmHg in
mid-to-late gestation) compared with the neonate (~60 mmHg) or adult
(~90 mmHg). Fetal heart rate is high (~180 beats/min in mid-to-late
gestation) when compared with the neonate (~100 beats/min) or adult
(~60 beats/min; Ref. 108). Acute hypotension in the fetus stimulates
a reflex response, which often includes both bradycardia and
vasoconstriction (11, 106, 115). The vasoconstriction is dependent on
increases in both sympathetic autonomic activity and the rate of
secretion of several vasoactive hormones, including arginine
vasopressin and the renin-angiotensin system. The increase in
peripheral resistance redistributes the combined ventricular output of
the fetus away from the metabolizing tissues of the fetal body and
preserves the flow within the umbilical-placental circulation.
Interestingly, the bradycardia appears to mimic the (ventricular C
fiber) response to rapid hemorrhage in the adult (79). It is possible
that, because fetal heart rate is relatively high in the resting state,
reductions in venous return are best compensated for by decreases in
fetal heart rate (to maximize diastolic filling). Despite the
similarities, however, the mechanism of the hypotension-stimulated
bradycardia of the fetus is different from that of the adult. The fetal
bradycardia is most likely caused by activation of the peripheral
chemoreceptors, not ventricular afferent nerves (112). It is important,
however, to point out that the fetal sheep does respond to mild
hypotension with small increases in heart rate. For example,
progressive hemorrhage can increase fetal heart rate (60, 115).
However, the degree of hypotension needed to produce bradycardia
appears to be much lower in the fetus than in the adult.
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FETAL ARTERIAL CHEMORECEPTORS |
Peripheral chemoreceptors are found within the fetal circulation in the
carotid sinuses and aortic arch (9). The afferent nerves from the
carotid sinus chemoreceptors travel within the carotid sinus nerves to
the glossopharyngeal nerves (cranial nerves IX), then on to synapse at
the nucleus of the solitary tract (NTS). The carotid sinus
chemoreceptors are active as demonstrated by direct nerve recordings
(8, 9). The arterial chemoreceptors of the fetal sheep produce a reflex
bradycardia when exposed to cyanide (59) or hypoxia (55, 56, 90, 117).
The evidence is clear that transient bradycardia in fetuses in utero,
especially during labor and delivery, is related to the activity of the
arterial chemoreceptors (55).
The late-gestation fetal sheep appears to be quite susceptible to
hypotension as a stimulus to bradycardia. This reflex bradycardia has
been demonstrated in response to hemorrhage (69, 70), vena caval
obstruction (112, 118), and vasodilator infusion (111). Although this
response has been proposed to be the result of cardiac receptor
activation, experimental evidence suggests that the response is
mediated by the arterial chemoreceptors (112). Vena caval obstruction,
a method that can be used to produce controlled decreases in venous
return and therefore combined ventricular output, stimulates decreases
in fetal heart rate, which are proportional to the induced decrease in
fetal arterial blood pressure (Fig. 2).
However, prior carotid sinus denervation prevents the heart rate
response (112). In other experiments, bilateral carotid occlusion
stimulated transient reductions in fetal heart rate in intact fetal
sheep (114). These studies suggest that the decrease in fetal arterial
blood pressure stimulates the arterial chemoreceptors by reducing the
blood flow through them. It is important to recognize that
interpretation of many denervation and physiological stimulation experiments is complicated by the fact that carotid sinus and aortic
arch denervation procedures eliminate afferent fibers from both
baroreceptors and chemoreceptors and that reductions in blood pressure
can both reduce baroreceptor activity and increase chemoreceptor activity. Because there is no "clean" method of eliminating one set of receptors without altering the function of the other, the interpretation of the relative roles of chemoreceptors and
baroreceptors in the control of fetal cardiovascular function must be
based on multiple approaches and information obtained from multiple experiments.
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Fig. 2.
Relationship between changes in heart rate and changes in mean arterial
pressure (MAP) in intact (INT;  and solid regression line) and
sinoaortic-denervated (SAD;  and dashed regression line) fetuses
during a 10-min period of hypotension produced by vena caval
obstruction. Significant relationship between these variables during
vena caval obstruction was abolished by SAD. [Borrowed with
permission (112)].
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FETAL ARTERIAL BARORECEPTORS |
The arterial baroreceptors are active in late-gestation fetal sheep.
The stimulus-response characteristics of these receptors suggest that
they are more responsive to increases than to decreases in fetal
arterial blood pressure (8, 9). Indeed, the reflex heart rate response
to acute hypertension is blocked by prior denervation of the carotid
sinus and aortic arch baroreceptors (57, 58).
In adult animals, sinoaortic denervation acutely increases arterial
blood pressure but chronically produces a near-normal arterial blood
pressure with a large increase in the minute-to-minute variability in
blood pressure (32). The role of the arterial baroreflex in the adult
is therefore to defend blood pressure against short-term challenges but
not to control blood pressure in the longer term. Despite the fact that
fetal arterial blood pressure is regulated at levels that are lower
than in the adult, this concept holds true in the late-gestation fetal
sheep. Chronic sinoaortic denervation does not produce substantial
changes in fetal arterial blood pressure (27, 57, 112, 119) but does increase the variability in fetal arterial blood pressure (57, 119).
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ATRIAL RECEPTORS |
In adult mammals, cardiovascular and endocrine reflex response
variables are influenced by the activity of the receptors located in
the atria and at the atrial-caval junctions (31, 82). Atrial receptors,
specifically, have well-documented inhibitory effects on the rate of
secretion of renin, AVP, and ACTH (3, 5, 6, 44, 97, 98). Responses to
nonhypotensive hemorrhage in the adult are heavily influenced by
cardiac receptors (3, 19). The relative importance of the atrial
receptors is quite different in the fetus. It appears that the atrial
receptors are not physiologically important with regards to control of
endocrine variables in the late-gestation fetal sheep. In contrast to
the adult, in which bilateral vagotomy blocks or inhibits the AVP, ACTH, and adrenal corticosteroid response to hemorrhage (43, 97),
bilateral vagotomy has no effect on the magnitude of the endocrine
response to hemorrhage in late-gestation fetal sheep (115). Indeed,
blockade of all cardiac receptors with a subpericardial injection of
procaine has little effect on circulating hormone concentrations and
has no effect on the magnitude of the endocrine response to hemorrhage
(25, 26).
It is not known when or how the atrial receptors become functionally
important. There are no published studies that report the response
characteristics of the atrial receptors in fetal or newborn sheep and
there are no studies that demonstrate the CNS effects of controlled
stimulation of the atrial receptors. It is possible that the atrial
receptors gain physiological importance after birth as a consequence of
neuronal maturation, either in the peripheral receptors themselves or
within the fetal brain stem. However, it is also possible that the
atrial receptors become active as a consequence of the rearrangement of
the circulation at birth. In the transition from intrauterine to
extrauterine life, the circulation loses its fetal characteristics with
the closure of the foramen ovale, the ductus arteriosus, and the ductus venosus (93). The decrease in pulmonary vascular resistance and the
closure of the ductus arteriosus combine to increase left atrial
pressure relative to the right. The increase in left atrial pressure
closes the foramen ovale, effectively separating the right and left
atria. It is possible that, before birth, the neuroanatomical pathways,
which include atrial receptors and their central connections, might be
intact and that they might be effectively activated by the increase in
atrial volume that accompanies the closure of the ductus venosus.
Resolving this issue will require new experiments but will be important
in terms of understanding the responsiveness to hemorrhage in the
peripartal period.
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VENTRICULAR RECEPTORS |
One of the most robust and dramatic physiological reflexes is the
Bezold-Jarisch reflex, the bradycardia that is stimulated by the
intravenous injection of veratrum alkaloids (123). The intravenous
injection of alkaloid stimulates the activity of the ventricular C
fiber afferents from the cardiac ventricles, which, in turn, stimulates
a reflex increase in the vagal efferent activity, which slows heart
rate (123). Although few details concerning ventricular receptor
function in fetal animals are known, available evidence suggests that
this reflex is slow to develop in the fetus (78). It is likely that the
overall control of the fetal cardiovascular system does not rely on the
activity of the ventricular receptors. Nevertheless, input from these
receptors might be more important during the process of parturition, a
time in which they are likely to be more mature and a time during which
there are likely to be physiologically important changes in venous
return and cardiac end-systolic volume.
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HORMONAL RESPONSE VARIABLES |
Endocrine responses to cardiovascular perturbation in the fetus are
homeostatic. That is, proper control of fetal arterial blood pressure
and distribution of combined ventricular output requires the responses
of several endocrine systems acting in concert with the autonomic
nervous system. Perhaps best studied in this regard are the
renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP).
RAAS responses to hypotension and hypoxia are mediated at least in part
by arterial baroreceptors and chemoreceptors. Plasma renin activity
(PRA) responses to hypotension produced by a 10-min period of vena
caval obstruction are proportional to the degree of hypotension (Fig.
3; Refs. 112, 118). The mechanism of this response is presumably similar to the PRA response to infusion of
vasodilator (111) or hemorrhage (115). The response to vena caval
obstruction is partially blocked by prior sinoaortic denervation, demonstrating the role of baroreceptors and/or chemoreceptors in this
response (112). However, the PRA response to hypotension is not
entirely reflex in nature. It is likely that the intrarenal baroreceptor plays an important role in the response to changes in
arterial blood pressure.
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Fig. 3.
Relationships between changes in MAP during vena caval obstruction (10 min, from 0 to 10 min) and changes in plasma concentrations of ACTH,
cortisol, and arginine vasopressin (AVP) and plasma renin activity
(PRA) in intact (left) and SAD
(right) fetuses. SAD attenuated
these hormonal responses to vena caval obstruction. [Borrowed
with permission (112)].
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The RAAS is also responsive to changes in blood gases (Fig.
4). Hypoxia, hypercapnia, and asphyxia
stimulate renin secretion in the fetal sheep (91, 117). The renin
response to hypoxia is relatively weak (91). Nevertheless, the
relatively small renin response to hypoxia and/or hypercapnia is
attenuated (but not eliminated) by sinoaortic denervation (117).
Although the RAAS response to hypoxia, hypercapnia, and transient
asphyxia is small, it is possible that asphyxia or hypotension severe
enough to produce ischemia of the arterial chemoreceptors might
be sufficient to stimulate substantial RAAS responses.
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Fig. 4.
Relationships between PRA (left) and
plasma ANG II (right) to arterial pH
in intact and SAD fetal sheep during hypoxia and hypercapnia. Linear
regressions in SAD fetuses were not statistically significant.
[Borrowed with permission from C. E. Wood, C. Kane, and H. Raff.
Peripheral chemoreceptor control of fetal renin responses to hypoxia
and hypercapnia. Circ. Res. 67: 722-732, 1990 (117)].
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AVP responses to hypotension are partially mediated by the arterial
baroreceptors. Analogous to the RAAS response to arterial baroreceptor
input, the AVP responses to vena caval obstruction are attenuated by
sinoaortic denervation (112). AVP responses to hypotension are
vigorous, often increasing plasma concentrations from ~2-5 pg/ml
to concentrations near 1,000 pg/ml (104). In contrast, the AVP
responses to hypoxia are relatively small, increasing concentrations to
~30-50 pg/ml (89, 90). It is somewhat counterintuitive that AVP
responses to hypoxia are not attenuated by sinoaortic denervation (89).
Rather, the AVP response to hypoxia appears to be mediated by the
generation of adenosine, because blockade of adenosine receptors
inhibits the AVP response (64).
Hemorrhage, hypotension, hypoxia, hypercapnia, and asphyxia in the
fetus are probably best thought of as integrative stimuli, because they
cannot in reality be separated from each other. Hemorrhage, for
example, produces some degree of disturbance in fetal blood gases
because of an impairment of umbilical-placental blood flow (11, 54,
106, 115). Hypercapnia produces systemic vasodilation, which reduces
blood pressure, which, in turn, decreases arterial baroreceptor
activity (28). Conversely, hypoxia stimulates reflex increases in blood
pressure that would be expected to increase arterial baroreceptor
activity (8, 59). Thus each type of stimulus, whether primarily
hemodynamic or respiratory in nature, would be expected to produce a
mixed blood pressure/blood gas stimulus. The responses to these mixed
inputs to the fetal reflexes are not always predictable. A good example
of this is the stimulus of acute hypoxia: one might ask whether the
increased blood pressure that occurs as a result of the reflex response
to hypoxia modulates the reflex AVP and RAAS responses to the stimulus.
Interestingly, the answer to this question is that the RAAS response to
hypoxia is not modulated significantly by the concomitant period of
hypertension (90). AVP responses, on the other hand, were significantly
attenuated by the increased blood pressure in fetuses between 115 and
127 days gestation (Fig. 5) but not in
older fetuses, between 129 and 136 days gestation. This is in contrast
to the situation in the adult animal (49). This observation suggests
that the input to the fetal brain from baroreceptors can be effectively
"ignored" during some physiological circumstances. This is
analogous to the lack of effect of arterial baroreceptor input during
exercise in the adult (18, 85) or to the adaptation of the CNS to the chronic lack of baroreceptor and chemoreceptor afferent traffic after
sinoaortic denervation (32, 57).
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Fig. 5.
Fetal arterial PO2, PRA, and AVP
responses to hypoxia (0-30 min) with () and without ()
simultaneous infusion of sodium nitroprusside (NiPr) to prevent reflex
transient hypertension that results from hypoxia.
A: data from a younger group of
fetuses (115-127 days gestation);
B: data from an older group of fetuses
(129-136 days gestation). Note that vasopressin response to
hypoxia was attenuated by arterial baroreceptor activity in younger
group of fetuses. * Different from 0 min within same group;
 greater AVP response to hypoxia as compared with young
fetuses without nitroprusside. [Borrowed with permission
(90)].
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CNS INTEGRATION OF REFLEX AFFERENT AND EFFERENT ACTIVITY |
There is a vast literature concerning CNS pathways controlling
cardiovascular function in adult animals, but there is relatively little information published on the fetus. Specifically, the integrity and development of these pathways and neuronal interconnections in
response to cardiovascular modifications are unknown in the fetus. This
short review cannot serve as a comprehensive review of this subject.
Nevertheless, it is perhaps useful to introduce the subject as a brief
overview and to identify the areas in which some progress has been made
in the fetus or neonate.
Baroreceptor afferent fibers project toward the brain in the
glossopharyngeal and vagus nerves (cranial nerves IX and X,
respectively) and synapse at the NTS in the medulla (37). The neurons
of the NTS project to various sites; however, the baroreflex control of
sympathetic tone is probably subserved by projections to the cells of
the so-called caudal ventrolateral medulla (CVLM). Within the CVLM,
these fibers synapse with GABAergic neurons, which, themselves, project
to the rostral ventrolateral medulla (RVLM). The neurons of the RVLM
that are inhibited by the release of GABA send projections in both
ascending and descending directions. Vasomotor tone is influenced by
descending projections to the intermediolateral column of the spinal
cord (IML), where they synapse with sympathetic preganglionic cells.
Vagal efferent tone is influenced by ascending projections to the
dorsal motor nucleus of the vagus and to the nucleus ambiguus.
Secretion of ACTH and AVP are influenced by projections from the RVLM
to the hypothalamus, especially direct projections to the
paraventricular nucleus (PVN) and supraoptic nucleus (SON) (50). The
secretion of AVP can also be affected by a polysynaptic pathway from
the NTS to the locus ceruleus, then on to the perinuclear region of the
PVN and SON, then to an inhibitory (GABAergic) interneuron, which
synapses with the PVN and SON (61). Throughout this basic pathway, the NTS and RVLM are essential for baroreflex control of sympathetic efferent tone and vasoactive hormone secretion (20, 37, 92, 100).
However, the activity of this reflex is influenced by input from other
regions. For example, inputs have been demonstrated from the
periaqueductal gray, the limbic system, the cerebellum, and the
cerebral cortex. There are also projections from the area postrema, a
circumventricular organ adjacent to the NTS, which allows influence by
circulating hormones such as ANG II (40, 41). Although this general
description of the baroreflex pathway is a gross simplification of a
complex integrated circuit, the activity and characteristics of the
neurons within the NTS, RVLM, CVLM, IML, and PVN can yield
important information concerning the basic function and modulation of
function in fetal animals. Overlaid on the basic neuronal circuitry are
the actions of various paracrine or autocrine modulators of neuronal
function. As previously mentioned, for example, adenosine modifies AVP
secretion, largely accounting for the AVP response to hypoxia in utero.
We have been interested in the potential modulatory effects of
prostanoids, given their synthesis in the fetus and the clinical
usefulness of prostaglandin synthase [cyclooxygenase (COX)]
inhibitors. We will argue below that prostanoids are important
modulators of the fetal CNS cardiovascular and endocrine control
mechanisms and that blockade of prostanoid biosynthesis might alter the
probability of fetal survival after stress in utero. Prostanoids have
actions both within the brain to directly alter neuronal function and indirectly via changes in cerebral blood flow (CBF). Complicating this
issue are the converse observations that
1) prostanoids alter cerebral
vascular tone and 2) the
biosynthesis of prostanoids within the cerebral circulation is altered
by changes in CBF. It is possible that the prostanoids generated within
the cerebral vasculature and/or within the brain interstitial fluid
modulate or even mediate some of the cardiovascular and endocrine
responses to fetal hypotension or fetal cerebral ischemia.
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PROSTANOID MODULATION OF FETAL CARDIOVASCULAR FUNCTION: EFFECTS
ON CEREBRAL PERFUSION |
Prostanoids are a class of compounds that we proposed could modulate
hormonal reflex responses to hypotension in the fetus. One site of
production of prostanoids is in the local cerebral vasculature during
cerebral hypoperfusion (22). In addition to being made by and released
into the vasculature, prostanoids are synthesized within neurons in the
brain of fetal sheep (63, 81). Physiologically, this endogenous
production of prostanoids can be demonstrated by central administration
of indomethacin to late-gestation fetal sheep at doses that
preferentially block prostaglandin synthesis in the CNS relative to
that in the peripheral circulation (62). CNS production of prostanoids
has also been demonstrated in response to the central injection of
cytokines (30).
In fetal and newborn animals, CBF is maintained during changes in
arterial blood pressure (23, 83, 107). In the fetal sheep, CBF is held
relatively constant during changes in arterial blood pressure between
45 and 80 mmHg (83, 88, 107). Therefore, decreases in arterial blood
pressure below the normally regulated level result in a decreased CBF.
Substantial physiological data in vivo point to a significant role for
dilator prostanoids in the regulation of cerebral vascular tone and CBF
in newborns (65, 67). Decreases in CBF can liberate arachidonic acid
(80, 109) and decrease cerebrovascular concentrations of dilator
prostanoids (86) and increase constrictor prostanoids (22).
PGE2 and
PGI2 are potent vasodilators,
whereas thromboxane A2
(TxA2) and
PGF2 are vasoconstrictors (24,
73-75, 110).
Inhibition of COX, an enzymatic step in arachidonic acid metabolism,
has an improvement effect on the outcome during cerebral ischemia. Indomethacin, a COX inhibitor, has been used for
pharmacologic closure of the patent ductus arteriosus (42, 45, 51), and it has a potential ability to prevent or attenuate the development of
intraventricular hemorrhage (2, 48, 71, 72). Free indomethacin crosses
the blood-brain barrier (4). It can be found in the brain within 30 min
of systemic administration (4). It is generally assumed that the
duration of action of indomethacin is long, but the plasma half-life is
relatively short and the cerebrospinal fluid concentration is closely
related to that of plasma (4). In piglets, indomethacin decreases CBF
at rest (66). These decreases in CBF occur concomitantly with decreases in cerebrospinal fluid levels of dilator PGs.
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PROSTANOID MODULATION OF FETAL CARDIOVASCULAR FUNCTION: EFFECTS ON
NEURONAL PROCESSING AND HORMONE SECRETION |
Prostanoids might alter cardiovascular function by affecting neuronal
processing within the CNS. For example, Breuhaus and coworkers
(13-15) and Cudd and Wood (33) have demonstrated that infusions of
PGE2 into the carotid arteries of
conscious adult sheep increase heart rate and blood pressure. This
effect is not mediated by an action of
PGE2 on arterial baroreceptor or
chemoreceptor afferent activity (13) and is therefore a direct effect
on the brain. PGE2 also has a
direct effect on the fetal brain to alter blood pressure and heart
rate, presumably by altering autonomic efferent tone (34). Analogously,
thromboxane also stimulates increases in arterial blood pressure and
heart rate by an action in regions perfused by carotid artery (116).
The concept of a neuronal action of prostaglandins within the fetal CNS
is likely not a new one. There is a rich history of experiments
demonstrating that PGE2 inhibits
fetal breathing movements (84, 99) during late gestation. Indomethacin,
which blocks prostanoid biosynthesis, increases the frequency of fetal
breathing movements (1). Indeed, it had been proposed that the source
of PGE2, which tonically inhibits
breathing movements in utero, was the placenta (103), although more
recent experiments suggest that the site of
PGE2 that affects fetal breathing
movements is the fetal CNS itself (77).
An important component of the effect of prostanoids on the
cardiovascular system is their effect on the hormones that, in turn,
influence blood pressure or fluid balance. It has been demonstrated that PGE2 has direct effect on the
fetal sheep pituitary gland by enhancing AVP-stimulated, but not
CRH-stimulated, ACTH secretion from dispersed fetal anterior pituitary
cells in culture (17). Young and Thorburn (122) found that
PGE2 has potent stimulatory actions on the late-gestation fetal sheep pituitary to increase both
the absolute concentration and the biologically active fraction of
ACTH-containing peptides in the fetal circulation. It also directly
stimulates glucocorticoid secretion from the fetal adrenal gland. It
has also been shown that PGE2
increases AVP secretion (53). Intracerebroventricular infusion of
PGE2 can stimulate ACTH and
cortisol secretion in fetal sheep (16), and treatment with indomethacin
decreases ACTH release (102). TxA2
is also a potential mediator of corticotropin-releasing factor (CRF)
release. In vitro treatment of adult rat hypothalami with U-46619 (a
TxA2 mimic) causes secretion of
CRF (7). We have found that TxA2 is a powerful and specific stimulator of ACTH secretion in both adult
and fetal sheep (35, 36, 116). In the adult sheep, endogenously
generated TxA2 stimulates ACTH
secretion (36) and, in the fetal sheep, infusions of U-46619 into the
carotid arterial blood supplying the fetal brain stimulates increases
in fetal ACTH secretion (116). The ACTH response to a stimulus that
causes TxA2 generation is blocked
through the inhibition of COX or through blockade of
TxA2-PGH receptor (35, 36).
We recently reported that inhibition of prostanoid biosynthesis
significantly and dramatically alters the fetal responsiveness to
hypotension. Indomethacin pretreatment significantly reduces the
magnitude of the ACTH and AVP responses to hypotension (104). It is
interesting that the effect of indomethacin on these responses to
hypotension requires intact baro- and chemoreceptive pathways. Prior
sinoaortic denervation itself somewhat reduces the magnitude of the
endocrine responses to hypotension. However, indomethacin does not
impose any further reductions in endocrine responsiveness (Fig.
6). This suggests to us that prostanoid
generation within the CNS augments the activity of this pathway.
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Fig. 6.
Fetal plasma ACTH, AVP, and cortisol responses to vena caval
obstruction in intact and SAD fetuses that had been pretreated
( 90 min) with 0.2 mg/kg indomethacin (Indo) or
phosphate-buffered vehicle (PB). Period of vena caval obstruction is
represented by hatched areas. Indomethacin significantly attenuated
both ACTH and AVP responses to hypotension. [Borrowed with
permission (104)].
|
|
The potential for prostanoids acting as neuromodulators within the
fetal brain is supported by the observation that both the constitutive
and inducible forms of prostaglandin endoperoxide synthase (PGHS-1 and
PGHS-2, alternatively COX-1 and COX-2) are found within fetal neurons
in regions important for cardiovascular and endocrine responses to
hypotension, hypoxia, and other cardiovascular "stresses" (38,
39, 77, 94). We have also recently reported the presence of
thromoboxane synthase in neuronal and glial cells in these regions
(52). It is also now known that various receptor subtypes for
prostanoids are also found within these regions of the brain (101).
Interestingly, it is also now recognized that both
PGE2 and
TxA2 can, in high concentrations,
inhibit the activity of the GABAA
receptor (96). It is conceivable that prostanoids might be generated
within GABAergic neurons or in GABA-receptive neurons themselves,
thereby altering reflex responsiveness to cardiovascular stimuli.
Supporting this general proposition is the observation that cerebral
hypoperfusion stimulates increases in the concentration of
PGE2 in the interstitial fluid of
late-gestation fetal sheep (105).
| |
OTHER MODULATORS OF FETAL CNS CONTROL |
There are several other potentially important modulators of fetal CNS
function that could significantly impact the control of the fetal
cardiovascular system. An obvious candidate is estrogen, an important
part of the steroid milieu that participates in the timing of
parturition in most, if not all, mammalian species. We have reported
that physiological increases in fetal plasma estradiol concentration
stimulate fetal ACTH secretion, both during basal conditions and in
response to hypotension (Fig. 7). This is
interesting in light of the rising concentrations of estrogen in the
fetal circulation at the end of gestation (21, 76). This increase in
estrogen concentration results from an induction of cytochrome
P-450c17
in the placenta of sheep or an increase in the rate of secretion of
dehydroepiandrosterone from the fetal adrenal of primates and accounts
for an important part of the "trigger" for parturition (68). It
is likely that this rising tide of estrogen in the fetus progressively
augments fetal ACTH secretion and progressively augments fetal CNS
responsiveness to stress. Interestingly, the source of estrogen that is
available for action within the fetal CNS is not limited to the
unconjugated steroids. The ovine fetal brain is richly endowed with
steroid sulfatase, the enzyme that deconjugates estrogen sulfates and makes the steroid available for action at the estrogen receptor (87).
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Fig. 7.
Fetal MAP (left) and fetal plasma
ACTH concentrations (right) before,
during, and after nitroprusside infusion in control
(top), estradiol
(middle, 250 µg/day)-, and
androstenedione (bottom, 250 µ/day)-treated fetuses after saline () or cortisol () infusion.
Note that ACTH scales are logarithmic. Estradiol treatment
significantly enhanced both basal and stimulated ACTH secretion.
Cortisol pretreatment reduced the fetal ACTH response to hypotension
~50% in both control and estradiol-treated fetuses, but negative
feedback was ineffective in androstenedione-treated fetuses.
[Borrowed with permission (95)].
|
|
| |
CONCLUSIONS |
Gaining a better understanding of the reflex and nonreflex mechanisms
controlling the fetal cardiovascular system is important because of the
interplay of blood pressure, umbilical-placental perfusion,
maternal-fetal gas exchange, and delivery of oxygen and substrate to
metabolizing tissue. Maintenance of fetal blood pressure is therefore
essential for fetal growth, development, and ultimate outcome. The
basic neuronal circuitry within the fetal brain that mediates
cardiovascular control is likely to be similar to that in the (better
studied) adult. However, an interesting and important aspect of this
system, which might be unique to the fetus, is the influence of various
autocrine, paracrine, and endocrine substances that modify the basic
reflex responsiveness and therefore alter the response to match the
demands of the developmental stage. Gaining a better understanding of
these interactions might therefore tell us much, not only about the
fetal cardiovascular system, but also perhaps about fetal growth and
development, survival of stress, and perhaps even about the control of parturition.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: C. E. Wood,
Dept. of Physiology, PO Box 100274, Univ. of Florida College of
Medicine, Gainesville, FL 32610-0274 (E-mail:
cwood{at}phys.med.ufl.edu).
| |
REFERENCES |
1.
Adamson, S. L.,
D. Engelberts,
and
K. J. Whiteley.
Low dose indomethacin via fetal vein or cerebral ventricle stimulates breathing movements in fetal sheep.
Can. J. Physiol. Pharmacol.
75:
135-142,
1997[Medline].
2.
Bada, H. S.,
R. S. Green,
M. Pourcyrous,
C. W. Leffler,
S. B. Korones,
H. L. Magill,
K. Arheart,
C. W. Fitch,
G. D. Anderson,
G. Somes,
K. Tullis,
and
J. Campbell.
Indomethacin reduces the risks of severe intraventricular hemorrhage.
J. Pediatr.
115:
631-637,
1989[Medline].
3.
Baertschi, A. J.,
D. G. Ward,
and
D. S. Gann.
Role of atrial receptors in the control of ACTH.
Am. J. Physiol.
231:
692-699,
1976.
4.
Bannwarth, B.,
P. Netter,
F. Lapicque,
P. Pere,
and
A. Gaucher.
Plasma and cerebrospinal fluid concentrations of indomethacin in humans.
Eur. J. Clin. Pharmacol.
38:
343-346,
1990[Medline].
5.
Bartter, F. C.,
and
D. S. Gann.
On the hemodynamic regulation of the secretion of aldosterone.
Circulation
21:
1016-1023,
1960[Abstract/Free Full Text].
6.
Bartter, F. C.,
I. H. Mills,
and
D. S. Gann.
Increase in aldosterone secretion by carotid artery constriction in the dog an its prevention by thyrocarotid arterial junction denervation.
J. Clin. Invest.
39:
1330-1336,
1960.
7.
Bernardini, R.,
A. Chiarenza,
A. E. Calogero,
P. W. Gold,
and
G. P. Chrousos.
Arachidonic acid metabolites modulate rat hypothalamic corticotropin releasing hormone in vitro.
Neuroendocrinology
50:
708-716,
1989[Medline].
8.
Blanco, C. E., G. S. Dawes, M. A. Hanson, and H. B. McCook. Stimulus-response
characteristics of chemoreceptors and baroreceptors in fetal and
newborn sheep. In: International Satellite Symposium
on Perinatal Physiology and Behaviour. Melbourne,
Australia, 1983.
9.
Blanco, C. E.,
G. S. Dawes,
M. A. Hanson,
and
H. B. McCooke.
Carotid baroreceptors in fetal and newborn sheep.
Pediatr. Res.
24:
342-346,
1988[Medline].
10.
Brace, R. A.
Fetal blood volume responses to acute fetal hemorrhage.
Circ. Res.
52:
730-734,
1983[Abstract/Free Full Text].
11.
Brace, R. A.,
and
C. Y. Cheung.
Fetal cardiovascular and endocrine responses to prolonged fetal hemorrhage.
Am. J. Physiol.
251 (Regulatory Integrative Comp. Physiol. 20):
R417-R424,
1986.
12.
Brace, R. A.,
and
C. Y. Cheung.
Fetal blood volume restoration following rapid fetal hemorrhage.
Am. J. Physiol.
259 (Heart Circ. Physiol. 28):
H567-H573,
1990[Abstract/Free Full Text].
13.
Breuhaus, B. A.,
and
J. E. Chimoskey.
PGE2 does not act at carotid sinus to raise arterial pressure in conscious sheep.
Am. J. Physiol.
245 (Heart Circ. Physiol. 14):
H1007-H1012,
1983.
14.
Breuhaus, B. A.,
and
J. E. Chimoskey.
Mechanisms of tachycardia caused by intracarotid PGE2 in conscious ewes.
Proc. Soc. Exp. Biol. Med.
180:
353-358,
1985[Abstract].
15.
Breuhaus, B. A.,
K. T. Demarest,
and
J. E. Chimosky.
Comparison of intraventricular and intracarotid infusions of PGE2 in conscious sheep.
Am. J. Physiol.
256 (Regulatory Integrative Comp. Physiol. 25):
R685-R693,
1989[Abstract/Free Full Text].
16.
Brooks, A. N.
Prostaglandin E2 stimulates adrenocorticotrophin and cortisol secretion via a hypothalamic site of action in fetal sheep.
J. Dev. Physiol. (Eynsham)
18:
173-177,
1992[Medline].
17.
Brooks, A. N.,
and
F. Gibson.
Prostaglandin E2 enhances AVP-stimulated but not CRF- stimulated ACTH secretion from cultured fetal sheep pituitary cells.
J. Endocrinol.
132:
33-38,
1992[Abstract].
18.
Burger, H. R.,
M. P. Chandler,
D. W. Rodenbaugh,
and
S. E. DiCarlo.
Dynamic exercise shifts the operating point and reduces the gain of the arterial baroreflex in rats.
Am. J. Physiol.
275 (Regulatory Integrative Comp. Physiol. 44):
R2043-R2048,
1998[Abstract/Free Full Text].
19.
Carr, D. H.,
D. B. Jennings,
T. N. Thrasher,
L. C. Keil,
and
D. J. Ramsay.
Role of right heart receptors in the control of renin, vasopressin, and cortisol secretion in dogs.
Am. J. Physiol.
263 (Regulatory Integrative Comp. Physiol. 32):
R1071-R1077,
1992[Abstract/Free Full Text].
20.
Catelli, J. M.,
W. J. Giakas,
and
A. F. Sved.
GABAergic mechanisms in nucleus tractus solitarius alter blood pressure and vasopressin release.
Brain Res.
403:
279-289,
1987[Medline].
21.
Challis, J. R. G.,
and
J. E. Patrick.
Fetal and maternal estrogen concentrations throughout pregnancy in the sheep.
Can. J. Physiol. Pharmacol.
59:
970-978,
1981[Medline].
22.
Chemtob, S.,
K. Beharry,
J. Rex,
D. R. Varma,
and
J. V. Aranda.
Changes in cerebrovascular prostaglandins and thromboxane as a function of systemic blood pressure.
Circ. Res.
67:
674-682,
1990[Abstract/Free Full Text].
23.
Chemtob, S.,
K. Beharry,
J. Rex,
D. R. Varma,
and
J. V. Aranda.
Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets.
Stroke
21:
777-784,
1990[Abstract/Free Full Text].
24.
Chemtob, S.,
N. Laudignon,
K. Beharry,
J. Rex,
D. Varma,
L. Wolfe,
and
J. V. Aranda.
Effects of prostaglandins and indomethacin on cereral blood flow and cerebral oxygen consumption of conscious newborn piglets.
Dev. Pharmacol. Ther.
14:
1-14,
1990[Medline].
25.
Chen, H. G.,
and
C. E. Wood.
Cardiac receptors do not tonically inhibit vasopressin secretion in late-gestation fetal sheep (Abstract).
Physiologist
34:
240,
1991.
26.
Chen, H. G.,
and
C. E. Wood.
Cardiac receptors tonically inhibit renin secretion in late- gestation fetal sheep (Abstract).
FASEB J.
6:
A1525,
1992.
27.
Chen, H. G.,
and
C. E. Wood.
Reflex control of fetal arterial pressure and hormonal responses to slow hemorrhage.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H225-H233,
1992[Abstract/Free Full Text].
28.
Chen, H. G.,
and
C. E. Wood.
The adrenocorticotropic hormone and arginine vasopressin responses to hypercapnia in fetal and maternal sheep.
Am. J. Physiol.
264 (Regulatory Integrative Comp. Physiol. 33):
R324-R330,
1993[Abstract/Free Full Text].
29.
Claybaugh, J. R.,
and
L. Share.
Vasopressin, renin, and cardiovascular responses to continuous slow hemorrhage.
Am. J. Physiol.
224:
519-523,
1973.
30.
Coceani, F.,
I. Bishai,
D. Engelberts,
R. V. House,
and
S. L. Adamson.
Response of newborn and adult sheep to pyrogens: relation between fever and brain eicosanoid changes.
Brain Res.
700:
191-204,
1995[Medline].
31.
Coleridge, J. C. G.,
and
H. M. Coleridge.
Afferent vagal C fibre innervation of the lungs and airways and its functional significance.
Rev. Physiol. Biochem. Pharmacol.
99:
1-110,
1984[Medline].
32.
Cowley, A. W., Jr.,
J. F. Liard,
and
A. C. Guyton.
Role of the baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs.
Circ. Res.
32:
564-576,
1973[Abstract/Free Full Text].
33.
Cudd, T. A.,
and
C. E. Wood.
Does intracarotid PGE2 increase plasma ACTH concentration in concious adult ewes?
Am. J. Physiol.
261 (Endocrinol. Metab. 24):
E395-E401,
1991[Abstract/Free Full Text].
34.
Cudd, T. A.,
and
C. E. Wood.
Prostaglandin E2 releases ovine fetal ACTH from a site not perfused by the carotid vasculature.
Am. J. Physiol.
263 (Regulatory Integrative Comp. Physiol. 32):
R136-R140,
1992[Abstract/Free Full Text].
35.
Cudd, T. A.,
and
C. E. Wood.
Prostanoid cascade inhibition prevents cardiovascular and adrenocorticotropic responses to mineral acid infusion.
Am. J. Physiol.
264 (Regulatory Integrative Comp. Physiol. 33):
R1235-R1241,
1993[Abstract/Free Full Text].
36.
Cudd, T. A.,
and
C. E. Wood.
Thromboxane A2 receptor antagonism prevents the hormonal and cardiovascular responses to mineral acid infusion.
Am. J. Physiol.
267 (Regulatory Integrative Comp. Physiol. 36):
R1235-R1240,
1994[Abstract/Free Full Text].
37.
Dampney, R. A. L.
Functional organization of central pathways regulating the cardiovascular system.
Physiol. Rev.
74:
323-353,
1994[Free Full Text].
38.
Degi, R.,
F. Bari,
T. C. Beasley,
N. Thrikawala,
C. Thore,
T. M. Louis,
and
D. W. Busija.
Regional distribution of prostaglandin H synthase-2 and neuronal nitric oxide synthase in piglet brain.
Pediatr. Res.
43:
683-689,
1998[Medline].
39.
Degi, R.,
F. Bari,
N. Thrikawala,
T. C. Beasley,
C. Thore,
T. M. Louis,
and
D. W. Busija.
Effects of anoxic stress on prostaglandin H synthase isoforms in piglet brain.
Brain Res. Dev. Brain Res.
107:
265-276,
1998[Medline].
40.
Ferguson, A. V.,
and
J. S. Bains.
Actions of angiotensin in the subfornical organ and area postrema: implications for long term control of autonomic output.
Clin. Exp. Pharmacol. Physiol.
24:
96-101,
1997[Medline].
41.
Fitzsimons, J. T.
Angiotensin, thirst, and sodium appetite.
Physiol. Rev.
78:
583-686,
1998[Abstract/Free Full Text].
42.
Friedman, W. F.,
M. J. Hirschklau,
M. P. Printz,
P. T. Pitlick,
and
S. E. Kirkpatrick.
Pharmacologic closure of patent ductus arteriosus in the premature infant.
N. Engl. J. Med.
295:
526-529,
1976[Abstract].
43.
Gann, D. S.,
and
G. L. Cryer.
Feedback control of ACTH secretion by cortisol.
In: Brain- Pituitary-Adrenal Interrelationships, edited by A. Brodish,
and E. S. Redgate. Basel: Karger, 1973, p. 197-223.
44.
Gann, D. S.,
I. H. Mills,
and
F. C. Bartter.
On the hemodynamic parameter mediating increase in aldosterone secretion in the dog.
Federation Proc.
19:
6
TOP
ABSTRACT
INTRODUCTION
