Prostaglandin E2 enhances AVP-stimulated but not CRF-stimulated ACTH secretion from cultured fetal sheep pituitary cells

1992 ◽  
Vol 132 (1) ◽  
pp. 33-38 ◽  
Author(s):  
A. N. Brooks ◽  
F. Gibson
Keyword(s):  
Direct Action ◽  
Specific Interaction ◽  
Plasma Concentrations ◽  
Concomitant Administration ◽  
Late Gestation ◽  
Prostaglandin E ◽  
Pituitary Cells ◽  
Acth Secretion ◽  
Fetal Sheep ◽  
Fetal Plasma

ABSTRACT This study examined the ability of prostaglandin E2 (PGE2) to regulate ACTH secretion from cultured anterior pituitary cells of fetal sheep between days 130 and 140 of gestation (term = 145 days). Corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) induced dose-dependent (0·1–1000 nmol/l) increases in ACTH secretion from fetal sheep pituitary cells maintained in culture for 6 days, with AVP being significantly (P<0·01) more potent than CRF. PGE2 (1000 nmol/l) significantly (P<0·05) enhanced the ability of AVP, but not CRF, to stimulate ACTH secretion. However, PGE2 given alone (0·1–1000 nmol/l) had no effect on ACTH secretion. Concomitant administration of CRF and AVP induced a greater release of ACTH than after treatment with either peptide alone, a synergistic interaction which was unaffected by simultaneous administration of PGE2. These results provide evidence for a direct action of PGE2 on ACTH secretion from the fetal sheep pituitary gland via a specific interaction with AVP. This interaction may allow increased fetal plasma concentrations of PGE2, seen during late gestation, to stimulate fetal pituitary–adrenal maturation. Journal of Endocrinology (1992) 132, 33–38

scholarly journals Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation

1997 ◽  
Vol 152 (3) ◽  
pp. 379-386 ◽  
Author(s):  
M B Nicol ◽  
J J Hirst ◽  
D Walker ◽  
G D Thorburn
Keyword(s):  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Late Gestation ◽  
Emg Activity ◽  
Fetal Sheep ◽  
Plasma Progesterone ◽  
Fetal Plasma ◽  
Progesterone Synthesis ◽  
Progesterone Metabolites ◽  
Vascular Catheters

Placental progesterone synthesis exposes the fetus to high levels of progesterone and progesterone metabolites during late gestation which may influence fetal behaviour. To determine the role of maternal progesterone synthesis in the control of fetal arousal state and fetal breathing movements (FBM), the effect of raising and lowering maternal progesterone concentrations was examined in chronically catheterised fetal sheep. Fetal and maternal vascular catheters, fetal tracheal and amniotic fluid catheters as well as electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted between 118 and 122 days gestational age (GA). Progesterone, 100 mg, administered twice daily i.m. for 3 days (130–133 days GA) resulted in a marked elevation in maternal plasma progesterone concentrations (370 ± 121%, n=5, P<0·05), but had no effect on fetal plasma concentrations. Fetal EOG episodes and the duration of fetal behavioural arousal were significantly suppressed throughout the progesterone treatment period (74·4–81·1% and 58–65% respectively, P<0·05, n=5). Four ewes received Trilostane (25 mg i.v.), a 3β-hydroxysteroid dehydrogenase inhibitor, between 136 and 140 days GA. Maternal and fetal progesterone concentrations were significantly lowered by 60 min after treatment (19·8 ± 8·0% and 39·5 ± 24·3% respectively, P<0·05). The incidence of fetal EOG activity increased from a pretreatment level of 26·8 ± 1·5 min/h to 30·3 ± 2·8 min/h at 1–6 h and to 35·0 ± 1·7 min/h (P<0·05) during the 7–12 h after Trilostane treatment. The duration of FBM episodes was significantly higher at 1–6 h and 7–12 h after Trilostane treatment (19·5 ± 3·0 and 23·6 ± 5·5 min/h respectively, P<0·05) compared with pretreatment levels (11·2 ± 1·2 min/h). We conclude that increasing maternal progesterone levels suppresses fetal EOG activity and behavioural arousal, whereas reducing maternal progesterone synthesis leads to an elevation of EOG activity and FBM. Journal of Endocrinology (1997) 152, 379–386

Cortisol inhibits ACTH secretion in late-gestation fetal sheep

1991 ◽  
Vol 260 (2) ◽  
pp. R385-R388 ◽  
Author(s):  
C. E. Wood
Keyword(s):  
Negative Feedback ◽  
Plasma Cortisol ◽  
Sodium Succinate ◽  
Plasma Concentrations ◽  
Maternal Blood ◽  
Acth Secretion ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Acth Concentration ◽  
Negative Feedback Control

In sheep, parturition is initiated by an increase in fetal adrenal secretion of cortisol. In term fetuses, adrenocorticotropic hormone (ACTH) secretion is increased despite increasing plasma concentrations of cortisol. The present study was performed to investigate whether fetal ACTH secretion is under negative-feedback control by cortisol. Ten chronically catheterized fetal sheep (140 days gestation) were used in this study. Five were infused with hydrocortisone sodium succinate (10 micrograms/min) and five with 0.9% physiological saline for 5 h. Fetal and maternal blood samples were drawn at 1-h intervals. Infusion of hydrocortisone sodium succinate significantly increased fetal plasma cortisol concentration from 38.2 +/- 8.4 ng/ml to mean levels between 74.6 +/- 11.6 and 88.5 +/- 4.7 ng/ml. Fetal plasma ACTH concentration was significantly decreased from 129 +/- 36 to 31 +/- 5 pg/ml after 5 h of infusion. Infusion of saline did not alter fetal plasma cortisol or ACTH concentration. Neither of the infusions significantly altered maternal plasma concentrations of ACTH or cortisol, or fetal or maternal blood gases, or plasma concentrations of sodium or potassium. With one exception, all fetuses were born alive at 145 +/- 1 and 144 +/- 1 days gestation in the saline- and hydrocortisone sodium succinate-infused groups, respectively. The results of this study demonstrate that at 140 days gestation fetal ACTH secretion is under negative-feedback control by cortisol.

Corticosteroid-binding globulin (CBG) production by hepatic and extra-hepatic sites in the ovine fetus; effects of CBG on glucocorticoid negative feedback on pituitary cells in vitro

1995 ◽  
Vol 146 (1) ◽  
pp. 121-130 ◽  
Author(s):  
E T M Berdusco ◽  
K Yang ◽  
G L Hammond ◽  
J R G Challis
Keyword(s):  
Negative Feedback ◽  
Binding Capacity ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Free Cortisol ◽  
Corticosteroid Binding Globulin ◽  
Ovine Fetus ◽  
Acth Release

Abstract Plasma cortisol levels increase in fetal sheep during late gestation and this is associated with an increase in plasma corticosteroid-binding globulin (CBG) concentrations. However, the relative tissue sources of plasma CBG, the ontogeny of its biosynthesis and glycoform composition have not been established in the ovine fetus. Therefore we examined whether changes in plasma corticosteroid binding capacity (CBC) in fetal sheep during late gestation were associated with different patterns of glycosylation and reflected changes in tissue CBG expression. Since free cortisol is considered the bioactive fraction, we measured changes in the percent and absolute free cortisol in fetal plasma during late gestation. In order to examine whether CBG alters cortisol negative feedback at the level of the fetal pituitary, we also examined the effect of exogenous CBG in mediating the glucocorticoid-induced suppression of basal and corticotrophin-releasing hormone (CRH)-stimulated ACTH release from fetal pituitary cells in culture. The mean free cortisol concentration in plasma was not different between days 15 and 20 prior to parturition, and between 5 and 10 days prepartum, although it did rise between these times. Plasma CBC in chronically catheterized fetuses rose from 23·3 ± 4·6 ng/ml at day 115 to 86·5 ± 20·8 ng/ml at term and then decreased rapidly after birth. Between day 125 and day 140 of pregnancy approximately 10% of fetal plasma CBG was retarded by Concanavalin-A chromatography. This proportion increased at birth and attained adult values of >70% by one month of age. By Northern blotting the relative levels of CBG mRNA in the fetal liver did not change between days 100 and 125, then increased significantly at day 140, but declined at term and in newborn lambs. CBG mRNA was undetectable in total RNA from lung, kidney, hypothalamus and placentomes, but was present in the fetal pituitary at days 125 and 140. Reverse transcription-PCR was used to confirm the presence of CBG mRNA in pituitary tissue from term fetuses. In cultures of term fetal pituitary cells, added CBG attenuated the cortisol- but not the dexamethasone-mediated suppression of basal and CRH-stimulated ACTH release. We conclude that in fetal sheep there is an increase in the corticosteroid binding capacity of plasma during late pregnancy which regulates, in part, free cortisol levels in the circulation. The liver is the major site of CBG biosynthesis in the fetus and at least until day 140 of gestation the rise in plasma CBC is associated with an increase in hepatic CBG mRNA levels. The fetal pituitary was also established as a site of CBG production. Output of ACTH by cultured pituitary cells was inhibited by cortisol and this effect was diminished in the presence of added CBG. This study supports a role for systemic CBG in modulating the availability of cortisol to the fetal pituitary and suggests an additional way of modifying feedback effects of cortisol at the pituitary through its own production of CBG. Journal of Endocrinology (1995) 146, 121–130

scholarly journals Cortisol infusion in late-gestation hypothalamo-pituitary disconnected sheep fetus restores pituitary cell responsiveness to arginine vasopressin

2009 ◽  
Vol 296 (2) ◽  
pp. E300-E304 ◽  
Author(s):  
Luke C. Carey ◽  
Stephen B. Tatter ◽  
James C. Rose
Keyword(s):  
Signal Transduction ◽  
Arginine Vasopressin ◽  
Plasma Cortisol ◽  
Pituitary Cell ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Inositol 1,4,5 Trisphosphate ◽  
Sheep Fetus

Corticotrophs in the fetal sheep become increasingly responsive to arginine vasopressin (AVP) in late gestation. We previously reported that this may be due in part to corresponding increases in signal transduction (inositol 1,4,5-trisphosphate, IP3). These ontogenic changes are prevented by hypothalamo-pituitary disconnection (HPD), which also prevents fetal plasma cortisol concentrations from increasing in late gestation. This led us to hypothesize that cortisol is involved in mediating the changes in pituitary responsiveness. HPD was performed on fetal sheep at 120 days gestational age (dGA). Half of the HPD fetuses were infused with cortisol for 3 days beginning at 135–137 dGA (HPD+C). The remaining HPD fetuses and a group of sham-operated control fetuses were infused with saline. Pituitary cells were isolated and cultured. After 48 h, a subset of cells was stimulated with 100 nM AVP for 2 h, and the medium was collected for ACTH analysis. Another subset of cells was stimulated with 100 nM AVP for 30 min, and the formation of IP3 was determined. Plasma cortisol concentrations increased rapidly within the first 6 h after infusion (5.2 ± 1.9 to 29.7 ± 4.9 ng/ml) but did not increase thereafter. Cells from HPD+C and sham-operated fetuses secreted significantly more ACTH than those from HPD fetuses (% increase from control: 33.0 ± 8.8%, 47.9 ± 10.6%, and 11.9 ± 2.4%, respectively). IP3 formation was significantly increased in cells from HPD+C and sham-operated compared with HPD fetuses (% increase from control: 17.7 ± 4.4%, 18.9 ± 4.3%, and 4.6 ± 1.5%, respectively). These findings support the idea that cortisol plays a role in mediating the increase in pituitary responsiveness to AVP in the late-gestation fetal sheep.

Neuroendocrine regulation of pituitary–adrenal function during fetal life

1996 ◽  
Vol 135 (2) ◽  
pp. 153-165 ◽  
Author(s):  
AN Brooks ◽  
DM Hagan ◽  
DC Howe
Keyword(s):  
Plasma Concentrations ◽  
Adrenal Function ◽  
Late Gestation ◽  
Neuroendocrine Regulation ◽  
Fetal Life ◽  
Acth Secretion ◽  
Feedback Effects ◽  
Fetal Plasma ◽  
Fetal Organ ◽  
Organ Systems

Brooks AN, Hagan DM, Howe DC. Neuroendocrine regulation of pituitary–adrenal function during fetal life. Eur J Endocrinol 1996;135:153–65. ISSN 0804–4643 During late gestation there is a rise in the concentration of corticosteroids in the fetal circulation that is essential for the coordinated maturation of many fetal organ systems and is a key component in the endocrine pathway leading to the onset of birth. Fetal plasma concentrations of adrenocorticotrophin (ACTH) increase during late, gestation and this rise precedes the increase in plasma corticosteroids. Paradoxically, ACTH and cortisol concentrations increase concomitantly even though cortisol would normally be expected to exert negative feedback effects to inhibit pituitary ACTH secretion. Elucidating the neuroendocrine signals that cause the increase in fetal ACTH, despite the elevated concentrations of cortisol at this time, will therefore provide vital clues as to the trigger for fetal organ maturation and birth. This article describes the normal ontogeny of the hypothalamo–pituitary–adrenal axis, discusses the neuroendocrine signals that trigger the increase in fetal ACTH secretion and provides potential explanations for the concomitant rise in ACTH and cortisol. AN Brooks, MRC Reproductive Biology Unit, 37 Chalmers Street, Edinburgh, EH3 9EW, Scotland, UK

Maternal pinealectomy abolishes the diurnal rhythm in plasma melatonin concentrations in the fetal sheep and pregnant ewe during late gestation

1989 ◽  
Vol 120 (3) ◽  
pp. 459-464 ◽  
Author(s):  
I. C. McMillen ◽  
R. Nowak
Keyword(s):  
Diurnal Rhythm ◽  
Plasma Concentrations ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Late Gestation ◽  
Control Group ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Plasma Melatonin ◽  
Pregnant Ewe

ABSTRACT We have investigated the effect of pinealectomy of ewes in pregnancy on the presence of the diurnal rhythm in fetal and maternal plasma concentrations of melatonin. Six ewes were pinealectomized between 104 and 118 days of gestation. Fetal and maternal blood samples were collected during 24-h periods between 125 and 140 days of gestation in the pinealectomized ewes and in an intact control (n = 4). There was a significant diurnal rhythm in both fetal and maternal plasma concentrations of melatonin in the control group. In this group, the fetal and maternal plasma melatonin concentrations were significantly higher in the dark (128·4±6·2 and 192·2± 10·7 pmol/l respectively) than in the light (46·2 ± 4·2 and 25·8 ± 2·1 pmol/l respectively). However there was no diurnal rhythm in either the fetal or maternal plasma melatonin concentrations in the pinealectomized group between 125 and 140 days of gestation. In contrast to the control animals, there was also no light–dark difference in the fetal or maternal plasma melatonin concentrations in four pinealectomized animals sampled frequently in the 3–7 days preceding delivery (mean length of gestation 146·5 days). However, in the pinealectomized sheep there was a gradual increase in the combined light–dark fetal plasma melatonin concentrations during late gestation from 27·9 ± 2·8 pmol/l (at 15–20 days before delivery) to 95·2± 14·1 pmol/l on the day of delivery. We have therefore demonstrated that the maternal pineal is the major source of the diurnal rhythm in maternal and fetal plasma melatonin concentrations. However maternal pinealectomy does not appear to remove all the melatonin immunoreactivity from the maternal and fetal plasma in late gestation. Journal of Endocrinology (1989) 120, 459–464

Separate and joint effects of arginine and glucose on ovine fetal insulin secretion

1997 ◽  
Vol 272 (1) ◽  
pp. E68-E73 ◽  
Author(s):  
A. Gresores ◽  
S. Anderson ◽  
D. Hood ◽  
G. O. Zerbe ◽  
W. W. Hay
Keyword(s):  
Insulin Secretion ◽  
Plasma Concentrations ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Acute Hyperglycemia ◽  
Joint Effects ◽  
Fetal Plasma ◽  
Normal Glucose ◽  
Polynomial Response Surface ◽  
Ovine Fetal

To determine separate and joint effects of increases (delta) in fetal plasma concentrations of arginine (Af) and glucose (Gf) on fetal insulin (If) secretion (delta If), 15 late-gestation fetal sheep were given 5-min arginine bolus infusions (40, 86, 144, 201, and 402 mumol/kg estimated fetal wt) at 90 min of 120 min steady-state glucose clamps (basal Gf, basal + 0.6 mM Gf, and basal + 1.1 mM Gr), producing absolute and percent increases above basal Af of 25.8 +/- 1.3 microM (+33%), 50.9 +/- 6.3 microM (+66%), 83.8 +/- 7.1 microM (+108%), 122.1 +/- 9.4 microM (+156%), and 302.2 +/- 28.2 microM (+386%), respectively. Acute hyperglycemia alone produced an increase above basal If of 9 +/- I microU/ml (+80%) and 19 +/- 2 microU/ml (+170%) after basal + 0.6 mM Gf and basal + 1.1 mM Gf, respectively. Increasing values of delta Af showed separate but lesser effects on delta If, which were significant only at very high values of Af (> 100% above mean normal Af) unless marked hyperglycemia (1.5- to 2-fold normal) was also present, demonstrating joint effects of delta Af and delta Gf on delta If according to a best-fit inverse polynomial response surface. We conclude that physiological increases in Af at normal glucose concentrations are not a potent-stimulus to insulin secretion in fetal sheep.

scholarly journals Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

2010 ◽  
Vol 299 (1) ◽  
pp. R365-R370 ◽  
Author(s):  
Nathan Knutson ◽  
Charles E. Wood
Keyword(s):  
Nmda Receptors ◽  
Hpa Axis ◽  
Fetal Brain ◽  
Specific Inhibitor ◽  
Late Gestation ◽  
Cerebral Hypoperfusion ◽  
Prostaglandin E ◽  
Plasma Acth ◽  
Fetal Sheep ◽  
Fetal Plasma

Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep ( n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide ( n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5–7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E2 (PGE2) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE2, which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE2. We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response to NMDA-mediated glutamatergic stimulation.

Reflex control of fetal arterial pressure and hormonal responses to slow hemorrhage

1992 ◽  
Vol 262 (1) ◽  
pp. H225-H233 ◽  
Author(s):  
H. G. Chen ◽  
C. E. Wood
Keyword(s):  
Blood Pressure ◽  
Arterial Pressure ◽  
Plasma Concentrations ◽  
Blood Gases ◽  
Plasma Renin ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Peripheral Chemoreceptors ◽  
Fetal Plasma ◽  
Phenylephrine Infusion

Late-gestation fetal sheep respond to slow hemorrhage with increases in plasma concentrations of adrenocorticotropic hormone (ACTH), hydrocortisone, arginine vasopressin (AVP), and plasma renin activity (PRA) that correlate to the acidemia and hypercapnia also produced by hemorrhage. This study was designed to investigate the role of peripheral chemoreceptors in the mediation of these responses. Chronically catheterized fetal sheep were left intact or were subjected to bilateral section of cervical vagosympathetic trunks and carotid sinus nerves. At least 5 days after surgical preparation (between 121 and 138 days of gestation) fetuses were bled at a rate of 11 ml/10 min for 2 h. Denervated fetuses were studied with or without simultaneous infusion of phenylephrine. Denervation exaggerated the decrease in mean arterial pressure and arterial pH and the increase in arterial PCO2 during hemorrhage. Infusion of phenylephrine in the denervated fetuses prevented the decrease in blood pressure and reduced the magnitudes of changes in blood gases. Fetal plasma ACTH, hydrocortisone, and PRA responses to the hemorrhage were exaggerated in the denervated fetuses (not infused with phenylephrine) compared with the intact fetuses. Phenylephrine infusion attenuated the ACTH response and inhibited the AVP response but did not alter the PRA response. We conclude that the sectioned fibers are important for the maintenance of blood pressure and blood gases during hemorrhage and that the PRA, AVP, and ACTH responses to slow hemorrhage are not mediated by peripheral chemoreceptors.

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