| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Programa de Patología, Campus Oriente, Instituto de Ciencias Biomédicas, Facultad de Medicina (R.A.R., J.A.L., E.M.S.), International Center for Andean Research, Universidad de Chile, Santiago, Chile; The Physiological Laboratory, University of Cambridge (D.A.G.), Cambridge, United Kingdom CB2 3EG; and the Department of Obstetrics and Gynecology, University College London (H.H.G.M., M.A.H.), London, United Kingdom WC1E 6HX
Address all correspondence and requests for reprints to: Raquel A. Riquelme, Programa de Patología, Campus Oriente, Instituto de Ciencias Biomédicas, Facultad de Medicina, International Center for Andean Research, Universidad de Chile, Casilla 16038, Santiago 9, Chile.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In lowland fetal and newborn animals, a component of adrenocortical sensitivity is regulated via neural pathways. Stimulation of the preganglionic splanchnic sympathetic innervation to the adrenal glands markedly augments the adrenal cortisol response to exogenous ACTH in conscious hypophysectomized calves (2), and section of the splanchnic nerves attenuates the sensitivity of this steroidogenic response in both calves (3) and lambs (4). In late gestation fetal sheep, section of the carotid sinus nerves reduces the cortisol response to acute hypoxemia, without affecting the increase in plasma ACTH (5). Similarly, section of the splanchnic nerves attenuates the cortisol response to acute hypotension without affecting the increase in ACTH in fetal sheep (6). Therefore, Giussani et al. (5, 7) proposed that during acute stress in late gestation fetal sheep, a reflex arc initiated by the carotid chemoreceptors and mediated via splanchnic nerve efferents operates to increase cortisol secretion, either directly and/or by enhancing adrenocortical sensitivity to circulating ACTH.
In the fetus, blunting of adrenocortical sensitivity to circulating ACTH may be an appropriate adaptive response to prolonged episodes of hypoxemia, such as those associated with pregnancy at altitude, to protect sensitive maturing tissues from elevated plasma cortisol levels during fetal development. However, the question then arises as to how the altitude-adapted fetus can elicit an adequate cortisol response during a superimposed acute stress, such as may occur during labor and delivery. We propose that to elicit a cortisol response of appropriate magnitude in fetuses with blunted adrenocortical sensitivities, one strategy may be to increase acutely the gain of neural influences on adrenocortical function. Therefore, removal of neural influences on adrenocortical function may have more profound effects during acute stress in highland than in lowland species. The llama (Lama glama) is a species that has evolved under the influence of high altitude hypoxia and demonstrates genetic adaptations that persist even when animals are born and living at sea level (8, 9). This study tested the hypothesis that the llama fetus demonstrates a potent carotid chemoreflex influence on adrenocortical function during acute hypoxemia by investigating the effect on ACTH and cortisol responses to acute hypoxemia of carotid sinus nerve section during late gestation.
Some of the results reported in this study have been previously published as abstracts (10).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
350 days] (11) obtained from Lampa, a city 580 m above sea
level. Upon arrival in Santiago (585 m above sea level), the llamas
were housed in a open yard with access to food and water ad
libitum, and they were familiarized with the study metabolic cage
and the laboratory conditions for 1–2 weeks before surgical
instrumentation.
Surgical preparation
Maternal and fetal surgeries were carried out on consecutive
days using well established techniques previously described in detail
(9, 12). In brief, after food and water deprivation for 24 h, the
llamas were premedicated with atropine (1 mg, im; Atropina Sulfato,
Laboratorio Chile, Santiago, Chile). Polyvinyl catheters (id, 1.3 mm)
were placed in the maternal descending aorta and inferior vena cava via
a hindlimb artery and vein under light general anesthesia (10 mg/kg
ketamine, im; Ketostop, Drug Pharma-Invetec, Santiago, Chile) with
additional local infiltration of lidocaine (2% lidocaine
hydrochloride; Dimecaína, Laboratorio Beta, Santiago, Chile).
The catheters were then tunnelled sc to exit at the maternal flank.
The following day the fetuses were instrumented under maternal general anesthesia [5–7 mg/kg sodium thiopentone (Tiopental Sódico, Laboratorio Astorga, Santiago, Chile) for induction and 1% halothane in 50:50 O2 and N2O for maintenance] according to one of two protocols chosen at random. In the intact group (n = 6) after a midline laparotomy, a fetal hind limb was withdrawn through a small hysterotomy. Polyvinyl catheters (id, 0.8 mm) were inserted into the fetal aorta via a hindlimb artery and into the inferior vena cava via a hindlimb vein. The fetal head was exposed through a second hysterotomy, and a catheter (id, 0.8 mm) was inserted into a carotid artery. Another catheter was placed in the amniotic cavity. The uterine incisions were closed in layers, and all vascular catheters were filled with heparinized saline (200 IU heparin in 0.9% NaCl), plugged with a copper pin, exteriorized through a maternal flank, and kept in a pouch sewn onto the maternal skin. In the denervated group (n = 4), the same surgical procedures were followed, but, in addition, the fetal carotid sinus nerves were cut bilaterally, as previously described (9).
During surgery, all animals were continuously hydrated with warm 0.9% NaCl solution (15–20 ml/kg·h) to compensate for any fluid loss. At the end of surgery and daily after surgery for 5 days, 1 million U penicillin (Penicilina G Sodica, Laboratorio Chile) and 500 mg kanamycin (Canamicina Sulfato, Laboratorio Chile) were administered in the amniotic fluid via the intraamniotic catheter. After surgery, the animals were returned to the yard, and at least 4 days of postoperative recovery were allowed before the beginning of the experiments. Vascular catheters were maintained patent by daily flushing with heparinized saline.
All animal care procedures and experimentation were conducted in accordance with the Guiding Principles for Research Involving Animals and Human Beings of the American Physiological Society and The British Animals (Scientific Procedures) Act, 1986.
Experimental procedure
The experiments were based on a 3-h protocol divided into three
periods of 60 min: 1-h normoxia, 1-h hypoxemia, and 1-h recovery. A
transparent polyethylene bag was placed over the llama’s head into
which known concentrations of O2, N2 and
CO2 were passed at a rate of about 35 liters/min. After
1 h of breathing air (normoxia), fetal hypoxemia was induced by
reducing the maternal inspired fraction of O2 to reduce
fetal PaO2 to between 12–15 mm Hg (hypoxemia). Maternal
and fetal isocapnia were maintained by adding about 1% CO2
to the maternal inspirate. After the hour of fetal hypoxemia, the llama
was returned to breathing air for an additional 60 min (recovery).
Maternal and fetal arterial blood samples (0.5 ml) were taken after 15 and 45 min of normoxia, at 15-min intervals throughout the hypoxemic period, and after 15 and 45 min of recovery to measure arterial blood gases and pH (BMS 3 MKS Blood microsystem and PHM 73 Blood Gas monitor, Radiometer, Copenhagen, Denmark; measurements corrected to 39 C), percent saturation of hemoglobin, and hemoglobin concentration (OSMS hemoximeter, Radiometer). In addition, five 1.5-ml arterial blood samples were collected simultaneously from mother and fetus for measurement of maternal and fetal plasma concentrations of ACTH and cortisol. These blood samples were collected after 15 and 45 min of normoxia, after 15 (early) and 45 (late) min of hypoxemia, and after 45 min of recovery.
Blood samples for hormone analyses were collected under sterile conditions into syringes without anticoagulant and transferred into polypropylene tubes coated with EDTA (1 mg/ml) that were kept on ice. The samples were then centrifuged at 12,000 rpm for 1 min, and plasma was removed, aliquoted, and stored at -20 C until assayed. Hormone assays were performed within 2 months of plasma collection.
Hormone analyses
Maternal and fetal plasma ACTH and cortisol concentrations were
measured by RIA, as previously described (5).
ACTH. Plasma ACTH was measured in duplicate using a double
antibody 125I RIA. All reagents were purchased in kit form
from Diagnostics Products Corp. (Llambers, UK). Duplicate 100-µl
plasma samples were incubated with 100 µl anti-ACTH antiserum and 100
µl [125I]ACTH for 24 h. The bound and free hormone
fractions were separated by mixing with 1.0 ml second
antibody-polyethylene glycol solution. After centrifugation, the
precipitate was retained for counting. The interassay coefficients of
variation for three controls (26, 94, and 296 pg/ml) were 12.9%,
8.2%, and 6.7%, respectively. The lower limit of detection of the
assay (90% bound/free ratio) was 8 pg/ml. The anti-ACTH antiserum
showed 0.2% cross-reactivity against 
MSH and no detectable
cross-reactivity against ß-endorphin, neurotensin, substance P,
or somatostatin.
Cortisol. Plasma cortisol concentrations were measured in duplicate by RIA using tritium-labeled cortisol as tracer (13). Duplicate 50-µl plasma samples were mixed with an equal volume of sodium carbonate solution (1.7 M; pH 10.5) and extracted with 2 ml diethyl ether. After freezing, the ether was decanted and evaporated, and the residue was reconstituted in 500 µl PBS. Aliquots of varying volumes (depending on expected results from pilot studies) were removed, made up to 400 µl with PBS, and incubated with 16,000 dpm [1,2,6,7-3H]cortisol (Amersham International, Aylesbury, UK) and 100 µl anticortisol antiserum (Steranti, St. Albans, UK). Bound and free cortisol were separated using dextran-coated charcoal, and after centrifugation, a 500-µl aliquot was removed for measuring the radioactivity content. Recoveries averaged 90%. The interassay coefficients of variation were 11.2%, 7.4%, and 6.8% for three control plasma pools (18.7, 46.5, and 88.6 nmol/liter). The lower detection limit of the assay (90% bound/free ratio) was 30 fmol/ml. The anticortisol antiserum showed the following cross-reactivities: 21-deoxycortisol, 50.8%; 11-deoxycortisol, 15.3%, corticosterone, 2.8%, cortisone, 2.0%; deoxycortisone, less than 0.6%, aldosterone, less than 0.6%, progesterone, 2.4%; 17ß-estradiol, less than 0.6%; and estrone, less than 0.6%.
Fetal cardiovascular variables
Fetal heart rate, fetal arterial and venous blood pressures, and
amniotic pressure were recorded continuously during the experimental
protocol. Fetal combined ventricular output and adrenal blood flow were
measured after 45 min of normoxia and after 15 (early) and 45 (late)
min of hypoxemia by injection of radionuclide-labeled microspheres
(57Co, 113Sn, and 46Sc,
respectively; New England Nuclear, Boston, MA) into the inferior vena
cava. Reference samples were drawn from the fetal ascending and
descending aorta at a rate of 3.24 ml/min for 1.5 min (14).
On completion of the experiments, the llama was anesthetized with sodium thiopental iv and killed with saturated potassium chloride.
Measurements and calculations
Fetal arterial and venous pressures were corrected for amniotic
pressure. Fetal perfusion pressure was calculated by subtracting
corrected fetal venous pressure from corrected fetal arterial
pressure.
At postmortem, fetal tissues were dissected out. These tissues were
carbonized, ground into a course powder, and placed in labeled vials,
and any radioactivity was counted with a multichannel 
pulse height
analyzer (Mimaxi 5000, Packard, Downers Grove, IL).
Fetal combined ventricular output was calculated as the sum of blood flows to all organs. The distribution of blood flow during acute hypoxemia in the llama fetus was presented in detail previously (9). In the present study, only combined adrenal blood flow and mesencephalic blood flow are presented. Vascular resistance in the fetal adrenal and in the fetal mesencephalon were calculated by dividing fetal perfusion pressure at the times of microsphere injection by fetal adrenal and mesencephalic blood flows, respectively. In addition, fetal ACTH delivery to the adrenals and fetal cortisol delivery to mesencephalon were calculated at the times of microsphere injections by multiplying the measured hormone concentration by the respective organ blood flow.
Statistical analyses
Values for all variables are expressed as the mean ±
SEM. All measured variables were compared between normoxia
and hypoxemia/recovery using one way-ANOVA followed by the
Student-Newman-Keuls test or using Student’s t test for
paired data with the Bonferroni correction. Comparisons between
maternal and fetal plasma hormone concentrations or between intact and
denervated fetuses were made using Student’s t test for
unpaired data. For all statistical comparisons, differences were
considered significant at P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. During normoxia, values
for maternal pHa, PaO2, PaCO2, and hemoglobin
saturation and concentration were similar for both groups, although the
arterial O2 content was lower in mothers of
carotid-denervated fetuses. During hypoxemia, a similar decrease in
maternal PaO2 and hemoglobin saturation and a similar
increase in hemoglobin concentration were measured for both groups of
animals, although values for arterial O2 content during
hypoxemia were lower in mothers of carotid-denervated fetuses than in
mothers of intact fetuses. These changes during hypoxemia occurred
without alterations in maternal pHa or PaCO2 from baseline.
Any changes in maternal variables measured during hypoxemia returned to
normoxic levels during recovery in both groups of animals.
|
. During normoxia, all variables
were similar for intact and carotid-denervated fetuses. During
hypoxemia, PaO2 and hemoglobin saturation fell to similar
levels in both groups; however, the fall in arterial O2
content was larger in the carotid-denervated fetuses. An increase in
hemoglobin concentration was only detected in the intact group of
fetuses during hypoxemia. Although fetal PaCO2 values were
maintained during hypoxemia in both intact and carotid-denervated
fetuses, a fall in pHa occurred in both groups by the end of the
hypoxemic episode. Fetal pHa values remained depressed during the
recovery period in both groups. All other measured variables returned
to prehypoxemic levels in both intact and carotid-denervated
fetuses.
|
). In contrast, a pronounced increase in
fetal plasma ACTH concentrations was measured in both intact and
carotid-denervated fetuses during hypoxemia. The increase in fetal
plasma ACTH during hypoxemia was similar in intact and
carotid-denervated fetuses. However, although fetal plasma ACTH
concentrations fell toward normoxic levels in intact fetuses, fetal
plasma ACTH remained elevated in carotid-denervated fetuses during
recovery.
|
). Fetal plasma cortisol concentrations increased from baseline in early and late hypoxemia and remained elevated during the recovery period in intact fetuses. In contrast, despite elevated fetal plasma ACTH concentrations during both hypoxemia and recovery, fetal plasma cortisol concentrations remained unchanged from baseline throughout the experimental protocol in carotid-denervated fetuses.
Fetal cardiovascular changes
Perfusion pressure and heart rate. Detailed analyses of the
fetal cardiovascular changes during acute hypoxemia have been
previously reported (9). During normoxia, fetal perfusion pressure and
fetal heart rate were similar in intact and carotid-denervated groups
of fetuses. During acute hypoxemia, a rapid and transient fall in fetal
heart rate occurred in intact fetuses, but not in carotid-denervated
fetuses (Table 2). After the hypoxemic period, tachycardia was measured
in both intact and carotid-denervated fetuses. A transient increase in
fetal perfusion pressure was also measured during early hypoxemia in
both intact and carotid-denervated fetuses. Although fetal perfusion
pressure returned toward normoxic values in intact fetuses, it remained
elevated in carotid-denervated fetuses during recovery (Table 2).
Combined ventricular output, adrenal blood flow, and adrenal ACTH
delivery. During normoxia, values for fetal combined ventricular
output, combined adrenal blood flow, adrenal vascular resistance, and
delivery of ACTH to the fetal adrenals were similar in intact and
carotid-denervated fetuses (Fig. 2). During hypoxemia, fetal combined
ventricular output remained unchanged from baseline in both intact and
carotid-denervated fetuses. In contrast, a pronounced increase in
combined adrenal blood flow and a fall in combined adrenal vascular
resistance occurred in both groups of fetuses during early and late
hypoxemia. These changes were accompanied by an increase in ACTH
delivery to the fetal adrenals during hypoxemia that was similar in
intact and carotid-denervated fetuses (Fig. 2).
|
). During hypoxemia,
mesencephalic blood flow and vascular resistance were maintained in
both intact and carotid-denervated fetuses. In contrast, although a
sustained increase in cortisol delivery to the mesencephalon was
measured in early and late hypoxemia in intact fetuses, these increases
did not occur in carotid-denervated fetuses (Fig. 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The situation of moderate sustained hypoxia, such as that associated with residence at high altitude, constitutes an environmental stress that at one time was considered harmless to the fetus. However, more recent observations indicate that, although it does not immediately threaten the life of the fetus, moderate hypoxia produces long term effects on development (for reviews, see Refs. 15–17). Although such alterations often do not become apparent until postnatal life, it has been suggested (15, 16, 17) that these disturbances may have their origin in subtle changes that occur during fetal life. For example, the human hypothalamo-pituitary-adrenal system demonstrates pronounced functional disturbances during postnatal growth at altitude; the adrenal gland undergoes hypertrophy within the first week after birth and is hyperactive from early postnatal life into adulthood (18). However, the effects of high altitude on fetal adrenocortical function have been little addressed.
Acute stress in the adult and the fetus is accompanied by increased cortisol release from the adrenal cortex. In the sheep fetus, this has been demonstrated using acute hypotension (19, 20), acute hemorrhage (21, 22), and acute hypoxemia (5, 23, 24). Although increased cortisol release is assumed to be largely determined by an increase in the plasma ACTH concentration, independent observations in both fetal and postnatal animals suggest an important neural component to cortisol release that may be initiated by a carotid chemoreflex under situations of acute hypoxemia (see introduction). Our data suggest that this chemoreflex modulation of cortisol release during acute hypoxemia is greater in the llama fetus than in the sheep fetus, as carotid denervation not only attenuated [as in the sheep fetus (5)] but completely prevented the increase in cortisol release during acute hypoxemia in the llama fetus, without affecting the ACTH response. This difference between the sheep (5) and llama (present study) fetus is further highlighted when considering that 1) the magnitude and duration of hypoxemia were similar in the two studies; 2) although the sheep study was carried out at 0.9 of gestation, the llama study was carried out at 0.6–0.7 of gestation; and 3) plasma ACTH and cortisol concentrations in both studies were determined by the same RIA techniques.
Blunting of basal fetal adrenocortical sensitivity to ACTH during pregnancy at high altitude (1) suggests that to elicit a cortisol response of appropriate magnitude to a superimposed acute stress, such as may occur during labor and delivery, greater amounts of ACTH, an increased bioactivity of ACTH, and/or an acute increase in the sensitivity of the adrenal cortex to circulating ACTH during the period of acute stress are required. A greater chemoreflex influence on cortisol release during acute hypoxemia in the llama fetus than in the sheep fetus provides support for one of these strategies. Additional evidence suggests that high altitude may modify neural, rather than endocrine, regulation of adrenocortical function. First, adrenal glands of life-long human high altitude residents are larger than those of age- and socially matched lowland controls (25). Neural regulation of adrenal growth is well established (26), and it may be that this plays a key role in this effect. Secondly, sustained hypoxemia in the sheep fetus is associated with a return of plasma ACTH concentrations toward baseline and a persistence of elevated cortisol concentrations (27, 28), and the integrity of the splanchnic nerves is necessary to maintain this elevated cortisol level (29).
The mechanisms of neurally mediated influences on adrenocortical function remain unclear. Edwards and colleagues (30, 31) suggested that enhancement of the steroidogenic response to exogenous ACTH during stimulation of the splanchnic nerves may be accounted for in part by an increase in the rate at which ACTH is presented to the gland secondary to an increase in adrenal blood flow. However, the enhancement of the glucocorticoid output that occurs during splanchnic nerve stimulation exceeds that which may result from the rise in adrenal ACTH presentation (31). Furthermore, in the present study, section of the carotid sinus nerves in the llama fetus completely prevented the cortisol response to acute hypoxemia without affecting the increase in adrenal blood flow. Combined, these studies strongly support the idea that neural regulation of adrenal cortisol release can be mediated by mechanisms other than those purely acting via changes in adrenal blood flow. Several neuropeptides, including vasoactive intestinal polypeptide (32) and CRH (33), can stimulate an increase in adrenal glucocorticoid output, and intense CRH immunoreactivity has been demonstrated at the cortico-medullary interface of adrenal glands and the splanchnic nerves of fetal sheep in late gestation (34). However, as the administration of a CRH antagonist failed to reduce cortisol output during splanchnic nerve stimulation in hypophysectomized calves that were given ACTH, Jones and Edwards (33) did not favor a role for CRH in mediating the enhanced steroidogenic response during increased neural input to the adrenal cortex, at least in the calf.
Much of the ACTH in the fetal sheep pituitary and plasma is present in higher mol wt precursor forms of lower biological activity than ACTH, such as POMC (35). Processing of POMC to ACTH is gestation dependent (36) and is affected by situations of acute stress produced by hypoglycemia in man (37) and hemorrhage in adult dogs (38) or in fetal sheep in late gestation (39). Hence, the possibility exists that section of the carotid sinus nerves may affect the processing of POMC to ACTH and thus reduce the bioactivity of circulating ACTH in plasma during hypoxemia, but there have no studies to address this idea.
In the present study, section of the carotid sinus nerves prevented the increase in plasma cortisol but did not affect the increase in plasma ACTH concentrations or the fall in adrenal vascular resistance observed in intact llama fetuses during acute hypoxemia. These data suggest that there is no carotid chemoreflex component to ACTH release or increased adrenal blood flow during acute hypoxemia in the llama fetus. These results support the earlier observations of Itskovitz et al. (40) that sino-aortic denervation does not affect the increase in adrenal blood flow during hypoxemia in fetal sheep. These studies suggest that pituitary ACTH release and adrenal vascular responses during hypoxemia are mediated via local mechanisms rather than by chemoreflex responses.
Since carotid sinus nerve section in the llama fetus prevented an increase in plasma cortisol concentrations without affecting blood flow to the mesencephalon during acute hypoxemia, the increase in cortisol delivery to the mesencephalon calculated in intact fetuses during hypoxemia did not occur in carotid-denervated llama fetuses. This reveals a reduced negative feedback influence of cortisol at the hypothalamus and pituitary and may explain at least in part the persistence of elevated plasma ACTH concentrations in carotid-denervated llama fetuses during the recovery period.
In conclusion, carotid denervation in the llama fetus completely prevented a cortisol response to acute hypoxemia without affecting the increase in plasma ACTH concentrations or the fall in adrenal vascular resistance. These data suggest a potent chemoreflex influence on adrenal cortisol release during acute hypoxemia in the llama fetus. The llama fetus offers fruitful avenues for future research on the effects of high altitude on hypothalamo-pituitary-adrenal function.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received January 29, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A. S. Thakor and D. A. Giussani The Role of Calcitonin Gene-Related Peptide in the in Vivo Pituitary-Adrenocortical Response to Acute Hypoxemia in the Late-Gestation Sheep Fetus Endocrinology, November 1, 2005; 146(11): 4871 - 4877. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Imamura, H. Umezaki, K. M. Kaushal, and C. A. Ducsay Long-Term Hypoxia Alters Endocrine and Physiologic Responses to Umbilical Cord Occlusion in the Ovine Fetus Reproductive Sciences, April 1, 2004; 11(3): 131 - 140. [Abstract] [PDF]
|
|
|
|
 |
|
 R. A Riquelme, G. Sanchez, L. Liberona, E. M Sanhueza, D. A Giussani, C. E Blanco, M. A Hanson, and A. J Llanos Nitric oxide plays a role in the regulation of adrenal blood flow and adrenocorticomedullary functions in the llama fetus J. Physiol., October 1, 2002; 544(1): 267 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. Green Programming of Endocrine Mechanisms of Cardiovascular Control and Growth Reproductive Sciences, April 1, 2001; 8(2): 57 - 68. [Abstract] [PDF]
|
|
|
|
|
|
D A Giussani, R A Riquelme, E M Sanhueza, M A Hanson, C E Blanco, and A J Llanos Adrenergic and vasopressinergic contributions to the cardiovascular response to acute hypoxaemia in the llama fetus J. Physiol., February 15, 1999; 515(1): 233 - 241. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
