Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121±1 days of gestation (term ≈145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the α 1 -adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.

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Effect of NO, phenylephrine, and hypoxemia on ductus venosus diameter in fetal sheep

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.3.h1166 ◽

2000 ◽

Vol 279 (3) ◽

pp. H1166-H1171 ◽

Cited By ~ 46

Author(s):

Torvid Kiserud ◽

Takashi Ozaki ◽

Hidenori Nishina ◽

Charles Rodeck ◽

Mark A. Hanson

Keyword(s):

Nitric Oxide ◽

Carotid Artery ◽

Common Carotid Artery ◽

Umbilical Vein ◽

Ductus Venosus ◽

Adrenergic Agonist ◽

Fetal Sheep ◽

Vasoactive Substances ◽

Ultrasound Measurements

To study the regulation of the ductus venosus (DV) inlet in vivo, we measured the effect of vasoactive substances and hypoxemia on its diameter in nine fetal sheep in utero at 0.9 gestation under ketamine-diazepam anesthesia. Catheters were inserted into an umbilical vein and a fetal common carotid artery, and a flowmeter was placed around the umbilical veins. Ultrasound measurements of the diameter of the fetal DV during normoxic baseline conditions [fetal arterial Po2(Pao2) 24 mmHg] were compared with measurements during infusion of sodium nitroprusside (SNP; 1.3, 2.6, and 6.5 μg · kg−1· min−1) or the α1-adrenergic agonist phenylephrine (6.5 μg · kg−1· min−1) into the umbilical vein or during hypoxemia (fetal PaO2reduced to 10 mmHg). SNP increased the DV inlet diameter by 23%, but phenylephrine had no effect. Hypoxemia caused a 61% increase of the inlet diameter and a distension of the entire vessel. We conclude that the DV inlet is tonically constricted, because nitric oxide dilates it but an α1-adrenergic agonist does not potentiate constriction. Hypoxemia causes a marked distension of the entire DV.

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Inhibition of Brain Prostaglandin Endoperoxide Synthase-2 Prevents the Preparturient Increase in Fetal Adrenocorticotropin Secretion in the Sheep Fetus

Endocrinology ◽

10.1210/en.2008-0123 ◽

2008 ◽

Vol 149 (8) ◽

pp. 4128-4136 ◽

Cited By ~ 14

Author(s):

Jason Gersting ◽

Christine E. Schaub ◽

Maureen Keller-Wood ◽

Charles E. Wood

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Fetal Brain ◽

Brain Regions ◽

Acth Secretion ◽

Fetal Sheep ◽

Prostaglandin Endoperoxide ◽

Fetal Plasma ◽

Prostaglandin Endoperoxide Synthase

Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth. Recently, we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal ACTH secretion. The present study was designed to test the hypothesis that the preparturient increase in fetal ACTH secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase (PGHS)-2 (cyclooxygenase-2) in the fetal brain. We performed two studies in chronically catheterized fetal sheep. In the first study, we infused nimesulide or vehicle intracerebroventricularly (icv) into singleton fetal sheep and collected blood samples until spontaneous parturition. Nimesulide significantly delayed parturition, and inhibited fetal ACTH and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration. In the second study, we used twin fetuses. One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle. Nimesulide reduced brain tissue concentrations of prostaglandin estradiol, while not affecting plasma prostaglandin E2 concentrations, demonstrating an action restricted to the fetal brain. Nimesulide reduced PGHS-2 mRNA and increased PGHS-2 protein, while not altering PGHS-1 mRNA or protein in most brain regions, suggesting an effect of the inhibitor on PGHS-2 turnover and relative specificity for PGHS-2 in vivo. We conclude that the preparturient increase in fetal ACTH and proopiomelanocortin is dependent upon the activity of PGHS-2 in the fetal brain. However, we also conclude that the timing of parturition is not solely dependent upon ACTH in this species.

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Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

Brain Research ◽

10.1016/j.brainres.2007.07.089 ◽

2007 ◽

Vol 1176 ◽

pp. 18-26 ◽

Cited By ~ 13

Author(s):

Victor M. Pulgar ◽

Jie Zhang ◽

G. Angela Massmann ◽

Jorge P. Figueroa

Keyword(s):

Umbilical Cord ◽

Chronic Hypoxia ◽

Cardiovascular Responses ◽

Fetal Sheep

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Placental norepinephrine clearance: in vivo measurement and physiological role

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.269.1.e145 ◽

1995 ◽

Vol 269 (1) ◽

pp. E145-E149 ◽

Cited By ~ 2

Author(s):

L. Bzoskie ◽

L. Blount ◽

K. Kashiwai ◽

Y. T. Tseng ◽

W. W. Hay ◽

...

Keyword(s):

Production Rate ◽

Umbilical Vein ◽

Physiological Role ◽

Total Clearance ◽

Clearance Rates ◽

Fetal Sheep ◽

Fetal Plasma ◽

In Vivo Measurement ◽

A Site

The intrauterine clearance rate of catecholamines is higher than in newborn animals or in adults. The separate contributions of the fetus and placenta to this clearance are not known. The placenta is a site of expression of the amine plasma membrane transporters that mediate this process. To determine the physiological role of this placental transporter in vivo, we studied fetal sheep at 123 days with common umbilical vein (UV), fetal arterial (AO), and venous catheters. Tritiated norepinephrine ([3H]NE) was infused to determine the kinetics of placental and fetal NE appearance and clearance rates. Umbilical flow was determined by [3H]NE infusion. Placental and total (fetal-placental) NE clearance rates were determined by measurement of [3H]NE from simultaneously drawn UV and AO samples. Total clearance was 99 +/- 8 ml.kg-1.min-1. Placental fractional [3H]NE extraction was 21% and accounted for 48% of total clearance. Fetal plasma NE production rate was 85 +/- 20 ng.kg-1.min-1. We conclude that placental catecholamine clearance is an important metabolic function of the placenta. This mechanism for clearance of the high fetal production rate of catecholamines is vital for fetal homeostasis. We speculate that derangements in placental catecholamine clearance may explain the exaggerated adverse effects on the fetus of drugs like cocaine, which block catecholamine transport.

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In Vivo Evidence for Stimulation of Placental, Myometrial, and Endometrial Prostaglandin G/H Synthase 2 by Fetal Cortisol Replacement after Fetal Adrenalectomy

Endocrinology ◽

10.1210/endo.142.9.8371 ◽

2001 ◽

Vol 142 (9) ◽

pp. 3857-3864 ◽

Cited By ~ 2

Author(s):

W. X. Wu ◽

X. H. Ma ◽

N. Unno ◽

P. W. Nathanielsz

Keyword(s):

Plasma Cortisol ◽

Treated Group ◽

Late Gestation ◽

Premature Labor ◽

Indirect Pathway ◽

Fetal Sheep ◽

Fetal Plasma ◽

Estrogen Synthesis ◽

Stimulation Of

Abstract Fetal glucocorticoid-induced premature labor in sheep is an established model of premature labor. However, the pathways by which fetal cortisol triggers subsequent maternal endocrine changes, including enhanced PG synthesis, leading to labor are unclear. The current study was undertaken to determine whether cortisol administration to adrenalectomized fetuses to clamp fetal cortisol at levels present early in the late gestation rise, which are inadequate to produce labor, can stimulate placental, myometrial, and endometrial prostaglandin G/H synthase 2 mRNA and protein expression. At 109–113 d gestation, fetal sheep adrenals were removed (n = 8), or sham surgery was performed (n = 4). From d 6 postadrenalectomy, maternal and fetal plasma cortisol were determined daily by RIA. From d 7 postadrenalectomy, cortisol (4 μg/min) was continuously infused iv to four adrenalectomized fetuses. Endometrium, myometrium, and placentome were collected from all three groups of ewes (n = 4 for each group), and total RNA and proteins were extracted from each intrauterine tissue and analyzed by Northern and Western for prostaglandin G/H synthase 2 mRNA and protein. P45017α hydroxylase mRNA was analyzed in the placentome by Northern blot. Data were analyzed by ANOVA. Plasma cortisol levels remained low in sham-operated and adrenalectomized fetus, whereas during cortisol infusion to adrenalectomized and cortisol-treated fetuses, plasma cortisol increased to the late gestation level. After adrenalectomy, prostaglandin G/H synthase 2 did not change in any tissue studied. Fetal plasma cortisol replacement to late gestation levels increased prostaglandin G/H synthase 2 to levels similar to term levels in all three tissues. PGHS1 mRNA and protein did not change in any group studied. There was a minimal increase in P45017α hydroxylase mRNA in the placentome in the adrenalectomized and cortisol-treated group. Cortisol- induced labor further increased P45017α hydroxylase mRNA in the placentome compared with that in adrenalectomized and cortisol-treated animals. These data provide evidence for in vivo cortisol up-regulation of prostaglandin G/H synthase 2, but not PGHS1, in late gestation in the ovine placentome, myometrium, and endometrium. As stimulation of the estrogen biosynthetic pathway was minimal in the adrenalectomized and cortisol-treated group, these data provide support for the concept that cortisol has a direct effect on prostaglandin G/H synthase 2 expression in addition to its classical indirect pathway on prostaglandin G/H synthase 2 as a result of estrogen synthesis.

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Effect of hypophysectomy on plasma catecholamines and enkephalins in fetal sheep

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.2.e203 ◽

1993 ◽

Vol 265 (2) ◽

pp. E203-E209

Author(s):

C. L. Coulter ◽

I. R. Young ◽

G. Simonetta ◽

I. C. McMillen

Keyword(s):

Gestational Age ◽

Plasma Concentrations ◽

Plasma Catecholamines ◽

Plasma Norepinephrine ◽

Plasma Epinephrine ◽

Fetal Sheep ◽

Fetal Plasma ◽

Hypoxic Conditions

The aim of this study was to determine the effect of fetal hypophysectomy on the plasma concentrations of catecholamines and enkephalins in the fetal sheep between 120 and 140 days gestation under basal and hypoxic conditions. During basal conditions, there was no difference in the plasma concentrations of norepinephrine and epinephrine between intact and hypophysectomized groups. Fetal plasma norepinephrine concentrations were significantly increased during hypoxia in intact fetal sheep (7.2 +/- 2.2 pmol/ml, -15 min; 20.2 +/- 7.7 pmol/ml, 30 min) between 130 and 140 days, but after fetal hypophysectomy there was no significant norepinephrine response to hypoxia at this gestational age (4.7 +/- 1.3 pmol/ml, -15 min; 8.8 +/- 2.8 pmol/ml, 30 min). In contrast, fetal plasma epinephrine concentrations were significantly increased during hypoxia in both the intact (1.5 +/- 0.5 pmol/ml, -15 min; 3.3 +/- 1.7 pmol/ml, 30 min) and hypophysectomized groups (1.8 +/- 0.6 pmol/ml, -15 min; 6.8 +/- 4.1 pmol/ml, 30 min) between 130 and 140 days. During basal conditions, plasma concentrations of free Met-Enk were significantly less in hypophysectomized fetal sheep (170.8 +/- 34.3 pg/ml; 120-140 days) than in intact fetal sheep (305.6 +/- 47.3 pg/ml). There were no differences, however, in the fetal plasma concentrations of total Met-Enk between the intact (18.0 +/- 1.9 ng/ml) and hypophysectomized (16.9 +/- 2.6 ng/ml) groups. During hypoxia, there were no changes in the fetal plasma concentrations of either free or total Met-Enk in the intact or hypophysectomized groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of fetal ovine adrenalectomy on sympathetic and baroreflex responses at birth

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00056.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. R460-R467 ◽

Cited By ~ 10

Author(s):

Jeffrey L. Segar ◽

Timothy Van Natta ◽

Oliva J. Smith

Keyword(s):

Plasma Cortisol ◽

Late Gestation ◽

Renal Nerve ◽

Baroreflex Control ◽

Fetal Sheep ◽

Cesarean Section Delivery ◽

Fetal Plasma ◽

Arterial Blood ◽

Baroreflex Function ◽

Before And After

Studies were performed to test the hypothesis that the absence of adrenal glucocorticoids late in gestation alters sympathetic and baroreflex responses before and immediately after birth. Fetal sheep at 130–131 days gestation (term 145 days) were subjected to bilateral adrenalectomy before the normal prepartum increase in plasma cortisol levels. One group of fetuses ( n = 5) received physiological cortisol replacement with a continuous infusion of hydrocortisone (2 mg · day−1 · kg−1 for 10 days), whereas the other group received 0.9% NaCl vehicle ( n = 5). All animals underwent a second surgery 48 h before the study for placement of a renal nerve recording electrode. Heart rate (HR), mean arterial blood pressure (MABP), renal sympathetic nerve activity (RSNA), and baroreflex control of HR and RSNA were studied before and after cesarean section delivery. At the time of study (140–141 days gestation), fetal plasma cortisol concentration was undetectable in adrenalectomized (ADX) fetuses and 58 ± 9 ng/ml in animals receiving cortisol replacement (ADX + F). Fetal and newborn MABP was significantly greater in ADX + F relative to ADX animals. One hour after delivery, MABP increased 13 ± 3 mmHg and RSNA increased 91 ± 12% above fetal values in ADX + F (both P < 0.05) but remained unchanged in ADX lambs. The midpoint pressures of the fetal HR and RSNA baroreflex function curves were significantly greater in ADX + F (54 ± 3 and 56 ± 3 mmHg for HR and RSNA curves, respectively) than ADX fetuses (45 ± 2 and 46 ± 3 mmHg). After delivery, the baroreflex curves reset toward higher pressure in ADX + F but not ADX lambs. These results suggest that adrenal glucocorticoids contribute to cardiovascular regulation in the late-gestation fetus and newborn by modulating arterial baroreflex function and sympathetic activity.

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Biological Activity of 17β-Estradiol-3-Sulfate in Ovine Fetal Plasma and Uptake in Fetal Brain

Endocrinology ◽

10.1210/en.2002-220764 ◽

2003 ◽

Vol 144 (2) ◽

pp. 599-604 ◽

Cited By ~ 23

Author(s):

Charles E. Wood ◽

Kelly E. Gridley ◽

Maureen Keller-Wood

Keyword(s):

Hpa Axis ◽

Active Form ◽

Fetal Brain ◽

Late Gestation ◽

Biologically Active ◽

Fetal Blood ◽

Fetal Sheep ◽

Fetal Plasma ◽

Hpa Axis Activity

In sheep, the fetal hypothalamus-pituitary-adrenal axis plays a central role in the initiation of parturition. We have reported that estradiol dramatically increases the activity of the fetal hypothalamus-pituitary-adrenal (HPA) axis. Sulfoconjugated estrogens are known to circulate in high concentrations in fetal plasma. We have reported the expression and abundant activity of steroid sulfatase within the fetal brain regions important for HPA axis control, and we have proposed that sulfoconjugated estrogens in fetal plasma are deconjugated (and therefore converted to a biologically active form) in fetal brain. The present study was designed to test the hypothesis that exogenous estradiol-3-sulfate stimulates HPA axis activity in late gestation fetal sheep and that it is concentrated by fetal brain tissue. We infused estradiol-3-sulfate iv into fetal sheep (125–135 d gestation; term = 147 d) at rates of 0, 0.25, and 1.0 mg/d for 5 d and performed serial sampling of fetal blood before and at the end of the infusion periods. Infusions increased fetal plasma estradiol-3-sulfate concentrations and produced dose-related increases in HPA axis activity. The action of the steroid on the fetal brain was also demonstrated as dose-related increases in the abundance of Fos in fetal cerebellum. In a second study we measured the uptake of sulfoconjugated and unconjugated estrogen (estrone-3sulfate and estrone, respectively) into the fetal brain (124–128 d gestation) in vivo. Both forms of estrogen were concentrated in fetal brain, with the uptake of estrone greater than that of estrone-3-sulfate. We conclude that sulfoconjugated estrogens augment fetal HPA axis activity and that they can cross the fetal blood-brain barrier. We propose that in late gestation the large circulating pool of sulfoconjugated estrogen is a biologically important source of active hormone that might play a role in the timing of parturition in sheep.

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Fetal endocrine responses to prolonged reduced uterine blood flow are altered following bilateral sectioning of the carotid sinus and vagus nerves

Journal of Endocrinology ◽

10.1677/joe.0.1570149 ◽

1998 ◽

Vol 157 (1) ◽

pp. 149-155 ◽

Cited By ~ 6

Author(s):

PE Stein ◽

SE White ◽

J Homan ◽

L Fraher ◽

HH McGarrigle ◽

...

Keyword(s):

Blood Flow ◽

Angiotensin Ii ◽

Carotid Sinus ◽

Arterial Oxygen Saturation ◽

Cardiovascular Responses ◽

Arterial Oxygen ◽

Uterine Blood Flow ◽

Vagus Nerves ◽

Fetal Sheep ◽

Fetal Plasma

The present study examines the effect of carotid sinus/vagosympathetic denervation on fetal endocrine responses to prolonged reduced uterine blood flow (RUBF). Fetal sheep had vascular catheters inserted following bilateral sectioning of the carotid sinus and vagus nerves (denervated, n = 7) or sham denervation (intact, n = 7). Uterine blood flow was mechanically restricted at 126.1 +/- 0.7 days (mean +/- S.E.M.) for 24 h, decreasing arterial oxygen saturation by 47.3 +/- 2.6% (P < 0.01). Fetal plasma samples were obtained at -1, 3, 6, 12 and 24 h for subsequent analyses of arginine vasopressin (AVP), angiotensin II and catecholamines. The AVP response to prolonged RUBF was markedly attenuated in denervated fetuses (15.6 +/- 3.6 to 34.9 +/- 6.0 pg/ml) when compared with intact (10.0 +/- 1.4 to 127.3 +/- 28.4 pg/ml). In contrast, intact fetuses demonstrated no change in plasma angiotensin II concentrations with RUBF whereas denervated fetuses demonstrated a marked increase from 47.5 +/- 18.9 to 128.7 +/- 34.2 pg/ml. The norepinephrine and epinephrine responses to prolonged RUBF were attenuated in denervated fetuses (950.1 +/- 308.9 and 155.8 +/- 58.5 to 1268.3 +/- 474.6 and 290.6 +/- 160.2 pg/ml respectively) when compared with intact (1558.3 +/- 384.4 and 547.3 +/- 304.7 pg/ml to 3289.2 +/- 1219.8 and 896.8 +/- 467.8 pg/ml respectively). These results support a role for the peripheral chemoreceptors in mediating fetal endocrine responses to prolonged RUBF, which may in part lead to the altered cardiovascular responses observed in denervated fetuses under these conditions.

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Thyrotrophin-releasing hormone (TRH) and lung maturation

Reproduction Fertility and Development ◽

10.1071/rd9950443 ◽

1995 ◽

Vol 7 (3) ◽

pp. 443 ◽

Cited By ~ 7

Author(s):

GC Liggins

Keyword(s):

Fetal Lung ◽

Lung Maturation ◽

Rabbit Lung ◽

Glucocorticoid Treatment ◽

Fetal Sheep ◽

Thyrotrophin Releasing Hormone ◽

Releasing Hormone ◽

Fetal Plasma

Clinical trials of thyrotrophin-releasing hormone (TRH) in conjunction with antepartum glucocorticoid treatment in the prevention of respiratory distress syndrome is based on experimental evidence that fetal lung maturation is accelerated by exposure to raised concentrations of triiodothyronine (T3) in fetal plasma. Studies of fetal rat and rabbit lung in vitro show an inconsistent increase in surfactant synthesis in response to T3 and potentiation of the response to corticosteroid. Experiments with fetal rodents in vivo are difficult to interpret because of confounding effects of the procedures and the responses to T3 are variable. In fetal sheep, very high concentrations of T3 are without effect on lung maturation. These observations suggest that the action of TRH on the lung may be mediated at least in part by one of the numerous, non-hormonal pathways known to be stimulated by TRH, particularly the autonomic nervous system. Experiments in rats and sheep lend support to this possibility. It is concluded that available evidence is inadequate to determine the mechanism of action of TRH.

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