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-Adrenergic contribution to the cardiovascular response to
acute hypoxemia in the chick embryo
1 Department of Pediatrics and Research Institute GROW, Maastricht University, 6202 AZ Maastricht, The Netherlands; and 2 Department of Physiology, University of Cambridge, Cambridge CB2 3EG, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Fetal responses to
acute hypoxemia include bradycardia, increase in blood pressure, and
peripheral vasoconstriction. Peripheral vasoconstriction contributes to
the redistribution of the cardiac output away from ancillary vascular
beds toward myocardial, cerebral, and adrenal circulations. We
investigated the effect of 
-adrenergic receptor blockade on this
fetal response. Fluorescent microspheres were used to measure cardiac
output distribution during basal and hypoxemic conditions with and
without phentolamine treatment. Phentolamine altered basal cardiac
output distribution, indicating a basal -adrenergic tone, but this
was mainly noted at the earlier stages of incubation. During hypoxemia,
phentolamine prevented vasoconstriction in the carcass. At day
19 of incubation, the percent cardiac output distributed to the
carcass increased by 20% compared with a decrease in the control group
by 17%. Phentolamine markedly attenuated the subsequent redistribution
of the cardiac output toward the brain (from +102% in the control
group to 
25% in the phentolamine-treated group) and the heart (from
+196% in the control group to +69% in the phentolamine-treated
group). In the chick embryo, -adrenergic mechanisms contribute to
the maintenance of basal vascular tone and to the redistribution of the
cardiac output away from the peripheral circulations toward the brain
and heart during hypoxemic conditions.
fetus; hypoxia; avian; catecholamines; sympathetic nervous system
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE FETUS MAY BE EXPOSED to episodes of hypoxemia during development and, in particular, during the actual processes of labor and delivery (26). The mature mammalian fetus has developed protective mechanisms to survive such hypoxemic episodes, which include transient bradycardia, an increase in arterial blood pressure, and peripheral vasoconstriction (17, 21). Peripheral vasoconstriction largely contributes to the redistribution of the fetal cardiac output away from ancillary circulations toward the adrenal, myocardial, and cerebral vascular beds (18, 32).
The physiological mechanisms mediating these cardiovascular responses
involve neural and endocrine components. Studies in fetal sheep in late
gestation have shown that the initial peripheral vasoconstriction in
response to hypoxemia is part of a carotid chemoreflex that is mediated
via -adrenergic efferent pathways, inasmuch as it can be abolished
by carotid sinus nerve section (2, 18) or by
-adrenergic receptor blockade with phentolamine (18).
Once the carotid chemoreflex vasoconstriction is triggered, endocrine
agents such as catecholamines (22), arginine vasopressin (15), angiotensin II (20), and neuropeptide Y
(12) are released into the fetal circulation to maintain
peripheral vasoconstriction throughout the duration of the hypoxemic challenge.
Studies in fetuses of other species have shown that the contribution of
neuroendocrine mechanisms to the fetal cardiovascular responses to
acute stress may be modified by the intrauterine environment. For
example, the fetal llama, a species adapted to the chronic hypobaric
hypoxia of life at altitude (27), shows an intense
peripheral vasoconstrictor response to acute hypoxemia that is mediated
by upregulated -adrenergic mechanisms (16).
The redistribution of the cardiac output in response to acute hypoxemia
has also been documented in the chick embryo in the last half of the
incubation period (29). The cardiovascular responses to
acute hypoxemia in the chick embryo show a developmental pattern, with
peripheral vasoconstriction becoming progressively more intense by
day 19 of incubation (hatching = 21 days)
(29). Additional studies from our laboratory have reported
high concentrations of circulating catecholamines in response to acute
hypoxemia in the chick embryo relative to those measured in the sheep
fetus at comparable stages of gestation or incubation
(28). In addition, this plasma catecholaminergic response
to acute hypoxemia also becomes progressively larger with advancing
incubation time (28), and in vitro studies, using femoral
arteries isolated from chick embryos, have shown pronounced
1-adrenergic contractile responses that also increase
from day 15 to day 19 of incubation
(25). Therefore, previous studies largely support the
hypothesis that, in the chick embryo, peripheral vasoconstriction and
redistribution of the cardiac output away from ancillary circulations
are highly dependent on -adrenergic pathways. In the present study,
we have tested this hypothesis by investigating the effects of
treatment of the chick embryo with the -adrenergic receptor
antagonist phentolamine on the redistribution of the cardiac output in
response to acute hypoxemia at different stages of incubation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation. Fertilized eggs of White Leghorn chickens were maintained in a commercial incubator at 38°C and 60% humidity. At the desired incubation time, the eggs were transferred to a clinical infant incubator and catheterized as previously described in detail (30). Briefly, eggs were opened at the air cell and placed in a holder within a Plexiglas box. A polyethylene catheter stretched by heat to a diameter of 100 µm was inserted in a chorioallantoic vein. Clay was used to fix the catheter to the eggshell. Later, the catheter was used for injections of fluorescent microspheres and phentolamine or saline solution. Throughout the procedure, the O2 concentration in the box was maintained by supplied mixtures of warmed and humidified N2 and O2, delivered at a constant flow of 5 l/min.
Experimental protocol.
Sixty chick embryos were included in the study. At days 11, 15, and 19 of incubation, 10 chick embryos were
randomly assigned to a control group and 10 to an experimental group.
Cardiac output distribution was measured by injection of 15-µm
fluorescent microspheres (Fluospheres, Molecular Probes, Eugene, OR)
suspended in saline and 0.05% Tween 80 (1,000,000 spheres/ml). In each
control and each experimental group, at each stage of incubation, 0.04 ml (40,000 spheres) of the suspension of blue-green fluorescent
microspheres were injected for measurement of basal cardiac output
distribution. Thereafter, each control group was injected with saline
(0.9% NaCl), and each experimental group was treated with phentolamine (Sigma Chemical; 2.5 µg/g in 5 µl/g embryo). After 5 min, 40,000 orange fluorescent microspheres were injected to determine the effect
of -adrenergic receptor blockade on basal cardiac output distribution. After 1 min, acute hypoxemia was induced in the chick
embryo by changing the supplied gas mixture to 100% N2 for 5 min. Previous studies have shown that this regimen results in a fall
in the arterial PO2 of the chick embryo from
5.11 ± 0.38 to 1.20 ± 0.21 kPa (28). After 5 min of hypoxemia, 40,000 crimson fluorescent microspheres were injected
to determine the effect of -adrenergic receptor blockade on cardiac
output distribution during the hypoxemic challenge. At the end of the
experiment, 5 min after normoxia was reestablished, all chick embryos
were decapitated and the chorioallantoic membrane (CAM), brain, heart, lungs, intestine, liver, and yolk sac were dissected for measurement of
microsphere distribution (28). All experiments complied
with the Dutch law for animal experimentation.
Measurement of microsphere distribution. Organs and the remaining carcass were digested in test tubes in a 2 M ethanol-KOH solution. The microspheres were isolated from the homogenate by centrifugation, a method shown to result in recovery of ~100% of microspheres (36). The dye was extracted with 3 ml of 2-(2-ethoxyethoxy)ethylacetate, and the fluorescence was measured by fluorometry using a fluorospectrometer (model LS-50B, Perkin-Elmer). No correction for spectral overlap was used, since the excitation and emission spectra of the three dyes were well separated. The fraction of cardiac output that was directed to the tissue was expressed as the level of the fluorescence of the sample, corrected for background, divided by the sum of fluorescence of all tissues (28).
Analysis of data. All data were processed using SPSS statistical software. Values are means ± SE unless stated otherwise. Within-group comparisons were assessed for statistical significance using the Wilcoxon signed-ranks test. Between-group comparisons were assessed using the Mann-Whitney U-test and the Kruskal-Wallis test. For all statistical comparisons, significance was accepted when P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Basal cardiac output distribution.
Baseline data for cardiac output distribution are shown in Fig.
1. The data are from control and
experimental groups (n = 20 per incubation period)
before the injection of saline or phentolamine. Cardiac output was
largely distributed to the CAM and the carcass during basal conditions
at all stages of incubation studied (Fig. 1). With increasing
incubation time, the fractions of the cardiac output directed to the
heart, lungs, brain, intestine, and carcass increased, and those
directed to the yolk sac and CAM decreased (Fig. 1).
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Effect of -adrenergic receptor blockade on basal cardiac output
distribution.
At day 11, treatment of the chick embryo with phentolamine
during basal conditions led to an increase in the fraction of the cardiac output directed to the brain, heart, carcass, and intestines but no change in the fraction of the cardiac output directed to the
liver (Fig. 2). At day 15,
although the fraction of the cardiac output to the carcass still
increased after phentolamine treatment during basal conditions, the
increases to the heart and intestines fell outside significance, and,
in contrast to measurements at day 11, there was a fall in
the fraction of the cardiac output distributed to the brain and liver.
At day 19 of incubation, there was no significant increase
in the fraction of the cardiac output directed to any organ, and the
fall in cardiac output distribution to the brain and liver persisted
after treatment with phentolamine during basal conditions (Fig. 2).
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Effect of -adrenergic receptor blockade on cardiac output
distribution during acute hypoxemia.
With advancing incubation time, cardiac output was preferentially
distributed to the brain and heart at the expense of the liver, yolk
sac, intestines, and carcass during acute hypoxemia (Fig.
3). The percent changes in cardiac output
distribution are summarized in Table 1.
At day 11, treatment of the chick embryo with phentolamine
during acute hypoxemia diminished the increase in the fraction of
cardiac output directed to the lungs, reversed the increase in cardiac
output to the brain and liver, reduced the fall in cardiac output to
the yolk sac, and led to an increase in the fraction of cardiac output
directed to the carcass (Fig. 3). At day 15, treatment of
the chick embryo with phentolamine during hypoxemia produced changes
similar to those measured at day 11, except the fraction of
cardiac output directed to the heart was significantly diminished (Fig.
3). The greatest effect of treatment with phentolamine during acute
hypoxemia occurred at day 19 of incubation, when the
fraction of cardiac output directed to the heart was substantially
reduced and there was a pronounced reversal in the fraction of cardiac
output directed to the brain, intestines, and carcass.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study in the chick embryo shows that 1)
sympathetic -adrenergic tone plays an important role in the
distribution of cardiac output under basal conditions, 2)
increased sympathetic -adrenergic tone is largely responsible for
the redistribution of cardiac output in response to acute hypoxemia,
and 3) the contribution of the sympathetic -adrenergic
tone toward mediating the redistribution of cardiac output away from
the carcass toward the heart and brain during acute hypoxemia increases
with advancing incubation time.
The chick embryo, as an experimental model, offers the primary advantage to study the development of fetal cardiovascular responses to adverse conditions without the influence of maternal vasoactive factors. This is not the case for mammalian species, where, for instance, maternal corticosteroids released in response to hypoxemia might easily cross the placenta and influence the fetal cardiovascular responses to the challenge (3). On the other hand, the chick embryo experimental model also has some limitations. For example, it is not possible to obtain repetitive blood samples or to measure the absolute cardiac output and regional blood flows, primarily because of the small size of the embryos and the limited blood volume.
In the chick embryo, the presence of vascular - and 
-adrenergic
receptors has been reported from day 7 of incubation
(13). In addition, intravenous injection of epinephrine
and norepinephrine evokes an increase in heart rate and blood pressure
in the chick embryo from day 7 of incubation
(14). Adrenal medulla cells arise from the sympathetic
chains on day 5 of incubation (8), and
catecholamines are detected in very small amounts from that day in
allantoic fluid (4). In the adrenal gland, epinephrine concentrations are relatively low until day 15, after which
they increase markedly toward hatching (37). Catecholamine
concentrations in plasma have been reported in the chick embryo from
day 10 of incubation, as has an increase in the plasma
concentrations of norepinephrine in response to asphyxia at day
14 (10). Previous studies in the chick embryo from
our laboratory have described an ontogenic increase in catecholamine
release in response to acute hypoxemia (28) that parallels
the maturation of the peripheral vasoconstriction that aids the
redistribution of cardiac output in favor of vital organs in response
to acute hypoxemia (29). The present study shows that this
maturing redistribution in response to acute hypoxemia is substantially
altered by treatment of the chick embryo with the -adrenergic
receptor antagonist phentolamine in all age groups studied, but in
particular at day 19 of incubation, suggesting that the
mechanisms mediating the redistribution of cardiac output with
increasing development are highly dependent on -adrenergic activity
in the chick embryo.
Basal cardiac output distribution.
In the present study, at day 11 of incubation, the fractions
of cardiac output directed to the carcass, heart, lungs, brain, and
intestine increased under basal conditions after treatment of the chick
embryo with the -adrenergic receptor antagonist. Although the
differences are small, they suggest the presence of basal sympathetic
-adrenergic tone in these vascular beds at this time of incubation.
At day 15, only the fraction to the carcass increased, with
significant decreases in fractions directed to the brain and liver
after treatment with phentolamine. This could be explained as a
diversion of flow from these organs to the carcass. At
day 19, the increase in the fraction of cardiac output
directed to the carcass after phentolamine treatment was smaller than
at previous stages of incubation. In combination, these data suggest
that the contribution of the -adrenergic vascular tone under basal
conditions becomes less important with progression of the incubation
period. Comparable data from studies in the fetal llama show that
-adrenergic blockade with phentolamine at 0.6-0.7 gestation
resulted in significant increases in carotid and femoral artery blood
flows (16) under resting conditions. The same treatment in
0.8-gestation fetal sheep had no effect on basal carotid or femoral
blood flows (18). Together, these findings support the
concept that the vasoconstrictor contribution of sympathetic
-adrenergic tone is greater in the carotid and femoral circulations
under basal conditions earlier than later in gestation. However, the
comparison between experiments in fetal sheep and fetal llamas may not
be justified, particularly since the contribution of the -adrenergic
system is upregulated in the llama (16). Alternatively,
the lack of a significant increase in the fraction of cardiac output
directed to the carcass after phentolamine at day 19 of
incubation may represent the maturation of -adrenergic-independent
vasoconstrictor mechanisms that act to reduce blood flow in this
circulation, even in the absence of -adrenergic influences. A
possible candidate may be angiotensin II, which has been reported to
induce a greater pressor response under basal conditions in fetal sheep
near term than earlier in gestation (34).
Response to acute hypoxemia. In the present study, treatment of the chick embryo with phentolamine during acute hypoxemia completely prevented the redistribution of cardiac output in favor of the brain at all stages of incubation studied. Given the proportion of cardiac output distributed to the carcass under basal conditions, these results suggest that maintenance of cerebral blood flow during hypoxemia in the chick embryo is highly dependent on peripheral vasoconstriction, despite potential local vasodilator mechanisms, such as the production of nitric oxide and adenosine, which have been shown to be active in the sheep fetus (19, 24, 35).
Additional results presented in this study show that the fraction of the cardiac output directed to the heart is increased in response to acute hypoxemia but that, in contrast to the effect on brain blood flow, treatment of the chick embryo with the-adrenergic receptor
antagonist attenuated, but did not completely prevent, this response.
This suggests that coronary vasodilation is more dependent than
cerebral vasodilation on mechanisms other than those promoting
-adrenergic-mediated peripheral vasoconstriction. Such mechanisms
may include 2-adrenergic receptor stimulation (11) and local nitric oxide release induced by hypoxemia,
as shown in fetal sheep (31).
One study in late-gestation fetal sheep reported that blood flow to the
heart increased during acute hypoxemia, but in contrast to the present
study, myocardial blood flow increased further after fetal treatment
with phenoxybenzamine, another -adrenergic receptor antagonist
(32). In that study, blood flow to the heart was measured
~20 min after the onset of hypoxia in the presence of
phenoxybenzamine. Therefore, it is likely that the enhancement of
myocardial blood flow after treatment of the sheep fetus with the
-adrenergic antagonist may have been due to prolonged hypoxemia with
developing acidemia, promoting a greater recruitment of local vasodilator mechanisms. An alternative explanation is that the sheep
fetus may be more dependent than the chick embryo on local vasodilator
mechanisms to promote an increase in myocardial blood flow during acute hypoxemia.
Interestingly, in the present study, treatment of the chick embryo with
phentolamine had a progressively greater effect on the distribution of
the cardiac output to the carcass during acute hypoxemia with advancing
incubation time. Therefore, although treatment with phentolamine during
hypoxemia enhanced carcass blood flow at day 11, it mildly
reversed the fall in carcass blood flow at day 15, and it
markedly reversed this fall at day 19. Previously, we
reported an ontogenic increase in the magnitude of the peripheral
vasoconstriction during acute hypoxemia (29) and that
these changes paralleled the maturation of the plasma catecholaminergic
response to acute hypoxemia in the chick embryo (28). Past
data, together with the results of the present study, therefore suggest
a progressively larger contribution of sympathetic -adrenergic
neuroendocrine mechanisms mediating peripheral vasoconstriction during acute hypoxemia as the chick embryo approaches hatching. Maturation of this sympathetic -adrenergic-mediated vasoconstriction may reflect the development of an important defense mechanism that
helps redistribute cardiac output away from the periphery toward the
brain under adverse conditions during incubation in the chick embryo.
Perspectives
In the sheep fetus,-adrenergic activity may be increased by
neural and endocrine pathways. For example, increased sympathetic discharge, such as that induced by hypoxemia, results in norepinephrine release from sympathetic nerve endings (1). Sympathetic
stimulation of the splanchnic nerve also results in catecholamine
release from the adrenal medulla (7, 9). In addition,
hypoxia might stimulate the adrenal gland to release catecholamines
into plasma by a direct effect on chromaffin cells (33).
Jones et al. (23) showed that in fetal sheep the increase
in plasma epinephrine was totally abolished and that the increase in
norepinephrine was reduced 90% in response to hypoxemia after adrenal
demedullation. This suggests that in fetal sheep the increase in
circulating plasma catecholamines in response to hypoxemia
originates primarily in the adrenal medulla. Furthermore, in the sheep
fetus, the direct effect of hypoxia on epinephrine release from the
adrenal gland becomes less important toward full term, when sympathetic
innervation of the adrenal gland is complete (5, 6). The
present study showed that, in the chick embryo, phentolamine abolished
the fall in carcass blood flow in response to hypoxemia and that this
effect became progressively more marked as the chick embryo approached full term. However, the present study cannot discriminate whether the
maturation of the -adrenergic activity mediating the ontogenic increase in the peripheral vasoconstrictor response to acute hypoxemia in the chick embryo is of neural and/or endocrine origin, since phentolamine will antagonize both mechanisms. The origin of the increased -adrenergic activity during acute hypoxemia as the chick
embryo approaches full term is therefore unresolved and will be the
subject of subsequent investigations.
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ACKNOWLEDGEMENTS |
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We thank F. W. Prinzen (Department of Physiology) and J. Hekking (Department of Anatomy-Embryology) for valuable advice on the study.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. L. M. Mulder, Dept. of Pediatrics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands (E-mail: amul{at}skin.azm.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 February 2001; accepted in final form 16 August 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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  L. D. Longo and W. J. Pearce Fetal cerebrovascular acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease? Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R16 - R24. [Abstract] [Full Text] [PDF]
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D. A. Crossley II, W. W. Burggren, and J. Altimiras Cardiovascular regulation during hypoxia in embryos of the domestic chicken Gallus gallus Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R219 - R226. [Abstract] [Full Text] [PDF]
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K. Ruijtenbeek, J. G. R. De Mey, C. E. Blanco ;, and H. Ehmke The Chicken Embryo in Developmental Physiology of the Cardiovascular System: A Traditional Model with New Possibilities Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R549 - R551. [Full Text] [PDF]
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K. Ruijtenbeek, C. G. A. Kessels, E. Villamor, C. E. Blanco, and J. G. R. De Mey Direct effects of acute hypoxia on the reactivity of peripheral arteries of the chicken embryo Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R331 - R338. [Abstract] [Full Text] [PDF]
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D. Sedmera, P. Kucera, and E. Raddatz Developmental changes in cardiac recovery from anoxia-reoxygenation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R379 - R388. [Abstract] [Full Text] [PDF]
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H. Scholz Adaptational responses to hypoxia Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1541 - R1543. [Full Text] [PDF]
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A. L. M. Mulder, A. Miedema, J. G. R. De Mey, D. A. Giussani, and C. E. Blanco Sympathetic control of the cardiovascular response to acute hypoxemia in the chick embryo Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2002; 282(4): R1156 - R1163. [Abstract] [Full Text] [PDF]
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Significant difference (P < 0.05) compared with day 15.
