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

2002 ◽  
Vol 283 (2) ◽  
pp. R460-R467 ◽  
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.

Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy

1999 ◽  
Vol 276 (1) ◽  
pp. H248-H256 ◽  
Author(s):  
Nobuya Unno ◽  
Chi H. Wong ◽  
Susan L. Jenkins ◽  
Richard A. Wentworth ◽  
Xiu-Ying Ding ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Plasma Cortisol ◽  
Time Windows ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Long Term Study ◽  
Arterial Blood ◽  
Ovine Fetus

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109–114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120–126, 127–133, and 134–140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 μg/min) was infused intravenously in four ADX fetuses from day 7postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 ± 3.2 ng/ml (mean ± SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

Effects of increased cortisol concentration on ovine fetal leucine kinetics and protein metabolism

1995 ◽  
Vol 268 (6) ◽  
pp. E1114-E1122 ◽  
Author(s):  
J. R. Milley
Keyword(s):  
Protein Synthesis ◽  
Protein Metabolism ◽  
Plasma Cortisol ◽  
Cortisol Concentration ◽  
Late Gestation ◽  
Fetal Plasma ◽  
Plasma Cortisol Concentration ◽  
Arterial Blood ◽  
Leucine Kinetics ◽  
Ovine Fetal

Fetal protein accretion decreases as gestation progresses, primarily because protein synthesis decreases. Also, glucocorticoid primarily because protein synthesis decreases. Also, glucocorticoid concentrations increase late in gestation, and restraint of growth is one of the most consistently noted effects of glucocorticoids. Therefore, this study was done to determine whether fetal protein accretion is decreased by increased cortisol concentration and whether such an effect might be due to decreased protein synthesis or increased proteolysis. Six days after surgery, fetal leucine and protein metabolism was measured in eight pregnant ewes (114-119 days of gestation) at normal and elevated cortisol concentrations. Arterial blood leucine concentration, fetal leucine disposal rate, and exogenous leucine uptake were unaffected by cortisol infusion. Fetal leucine decarboxylation, however, increased by 19% (P < 0.001). Increased fetal cortisol concentration increased fetal proteolysis by 11% (P < 0.001) but did not affect the use of leucine for protein synthesis. Consequently, fetal protein accretion fell by 34% (P < 0.002). We conclude that increased fetal plasma cortisol concentration increases fetal proteolysis, thereby decreasing the rate of fetal protein accretion, an effect different from the decreased protein synthesis reported in late gestation.

Thyroid hormone modulates renin and ANG II receptor expression in fetal sheep

2005 ◽  
Vol 289 (4) ◽  
pp. R1006-R1014 ◽  
Author(s):  
Kai Chen ◽  
Luke C. Carey ◽  
Nancy K. Valego ◽  
Jingfang Liu ◽  
James C. Rose
Keyword(s):  
Thyroid Hormone ◽  
Receptor Expression ◽  
Late Gestation ◽  
Receptor Subtype ◽  
Ang Ii ◽  
Angiotensin Ii Receptor ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Active Renin ◽  
Arterial Blood

Fetal renin-angiotensin system (RAS) activity is developmentally regulated, increasing in late gestation toward term. At the same time, fetal hemodynamic parameters change, with blood pressure increasing and heart rate decreasing. During this period, fetal plasma thyroid hormone concentrations also increase significantly. In this study we utilized the technique of thyroidectomy (TX), which removes thyroid hormone from the circulation, to investigate the importance of thyroid hormone on the developmental changes in the RAS (in plasma, kidney, heart, and lung) and hemodynamic regulation in fetal sheep. TX was performed at 120 days of gestational age (dGA), and control fetuses were sham operated. Immediately before necropsy (∼137 dGA), fetuses were infused with isoproterenol and the hemodynamic responses were noted. TX significantly decreased plasma thyroid hormone concentrations and renal renin mRNA and renal active renin levels but did not change fetal plasma active renin levels. TX decreased both angiotensin II receptor subtype 1 (AT1) mRNA and protein levels in kidney and lung but not in the left ventricle. TX also was associated with increased ANG II receptor subtype 2 (AT2) mRNA and protein at the 44-kDa band in kidney, whereas AT2 protein was decreased at the 78-kDa level in kidney and lung tissue only. TX fetuses had significantly lower basal mean arterial blood pressures (MAP) and heart rates than controls. Isoproterenol infusion decreased MAP in TX fetuses. These findings support the hypothesis that thyroid hormone is important in modulating maturation of RAS and cardiovascular function in the late-gestation fetal sheep.

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep

2006 ◽  
Vol 291 (2) ◽  
pp. E214-E220 ◽  
Author(s):  
Luke C. Carey ◽  
Yixin Su ◽  
Nancy K. Valego ◽  
James C. Rose
Keyword(s):  
Regulatory Protein ◽  
Late Gestation ◽  
Mrna Levels ◽  
Acth Stimulation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Arterial Blood ◽  
Acth Receptor ◽  
Underlying Mechanisms

The late-gestation plasma cortisol surge in the sheep fetus is critical for stimulating organ development and parturition. Increased adrenal responsiveness is one of the key reasons for the surge; however, the underlying mechanisms are not fully understood. Our recent studies suggest that ACTH-mediated increased expression of ACTH receptor (ACTH-R) and steroid acute regulatory protein (StAR) may play a role in enhancing responsiveness. Hence, we examined effects of ACTH infusion in fetal sheep on mRNA expression of these two mediators of adrenal responsiveness and assessed the functional consequences of this treatment in vitro. Fetuses of ∼118 and 138 days of gestational age (dGA) were infused with ACTH-(1–24) for 24 h. Controls received saline infusion. Arterial blood was sampled throughout the infusion. Adrenals were isolated and analyzed for ACTH-R and StAR mRNA, or cells were cultured for 48 h. Cells were stimulated with ACTH, and medium was collected for cortisol measurement. Fetal plasma ACTH and cortisol concentrations increased over the infusion period in both groups. ACTH-R mRNA levels were significantly higher in ACTH-infused fetuses in both the 118 and 138 dGA groups. StAR mRNA increased significantly in both the 118 and 138 dGA groups. Adrenal cells from ACTH-infused fetuses were significantly more responsive to ACTH stimulation in terms of cortisol secretion than those from saline-infused controls. These findings demonstrate that increases in circulating ACTH levels promote increased expression of ACTH-R and StAR mRNA and are coupled to heightened adrenal responsiveness.

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

Endocrinology ◽  
2001 ◽  
Vol 142 (9) ◽  
pp. 3857-3864 ◽  
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.

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.

Effects of incremental cortisol and adrenalectomy on plasma corticosteroid binding capacity in fetal sheep

1995 ◽  
Vol 73 (11) ◽  
pp. 1568-1573 ◽  
Author(s):  
Treena M. Jeffray ◽  
Edward T. M. Berdusco ◽  
John R. G. Challis ◽  
Megan Wallace ◽  
Abigail Fowden
Keyword(s):  
Plasma Cortisol ◽  
Binding Capacity ◽  
Strong Support ◽  
Significant Rise ◽  
Late Gestation ◽  
Total Plasma ◽  
Individual Values ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Corticosteroid Binding Globulin

The effects of incremental cortisol infusion or fetal adrenalectomy on plasma corticosteroid-binding capacity (CBC) were examined in sheep fetuses during late gestation (term ≈ 150 days). Cortisol, infused from day 120 at 1.5 mg/day for the first 3 days, 2.5 mg/day for the next 5 days, and 3.5 mg/day for the final 2 days, stimulated a significant rise in plasma CBC and immunoreactive corticosteroid binding globulin (CBG). There was a significant positive correlation between individual values for total plasma cortisol concentrations and CBC values. In contrast, fetal adrenalectomy at day 115 prevented the rise in plasma CBC found in intact fetuses at term. These experiments show that exogenous cortisol, given in a manner that mimics the prepartum rise in fetal plasma cortisol, stimulates CBG biosynthesis, whereas abolition of the cortisol rise prevents the increase in CBG. The study provides strong support for the proposal that the prepartum increase in CBG biosynthesis in fetal sheep occurs in response to the progressive rise in adrenal cortisol output by the fetus towards term.Key words: corticosteroid binding globulin, cortisol, adrenalectomy, fetus, sheep.

scholarly journals Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep

2002 ◽  
Vol 283 (3) ◽  
pp. R669-R679 ◽  
Author(s):  
L. J. Edwards ◽  
I. C. McMillen
Keyword(s):  
Cardiovascular System ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Late Gestation ◽  
Rate Pressure Product ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Maternal Undernutrition ◽  
Arterial Blood ◽  
The Impact

It has been proposed that fetal adaptations to intrauterine nutrient deprivation permanently reprogram the cardiovascular system. We investigated the impact of restricted periconceptional nutrition and/or restricted gestational nutrition on fetal arterial blood pressure (BP), heart rate, rate pressure product, and the fetal BP responses to ANG II and the angiotensin-converting enzyme inhibitor captopril during late gestation. Restricted periconceptional nutrition resulted in an increase in fetal mean arterial BP between 115 and 125 days gestation (restricted 41.5 ± 2.8 mmHg, n = 12; control 38.5 ± 1.5 mmHg, n = 13) and between 135 and 147 days gestation (restricted 50.5 ± 2.2 mmHg, n = 8; control 42.5 ± 1.9 mmHg, n = 10) as well as an increase in the rate pressure product in twin, but not singleton, fetuses between 115 and 147 days gestation. Mean BP and fetal plasma ACTH were also positively correlated in twin, but not singleton, fetuses. This is the first demonstration that maternal undernutrition during the periconceptional period results in an increase in fetal arterial BP. This increase occurs concomitantly with an increase in fetal ACTH but is not dependent on activation of the fetal renin-angiotensin system.

scholarly journals Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol

2002 ◽  
Vol 172 (3) ◽  
pp. 527-534 ◽  
Author(s):  
KA Clarke ◽  
JW Ward ◽  
AJ Forhead ◽  
DA Giussani ◽  
AL Fowden
Keyword(s):  
Plasma Cortisol ◽  
Inverse Correlation ◽  
Hydroxysteroid Dehydrogenase ◽  
Plasma Cortisol Level ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Ovine Placenta ◽  
Cortisol Levels

The effect of fetal cortisol on the activity of the type 2 isoform of the enzyme, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), was examined in ovine placenta and fetal kidney by measuring tissue 11 beta-HSD2 activity during late gestation when endogenous fetal cortisol levels rise and after exogenous cortisol administration to immature fetuses before the prepartum cortisol surge. Placental 11 beta-HSD2 activity decreased between 128-132 days and term (approximately 145 days of gestation) in association with the normal prepartum increase in fetal plasma cortisol. Raising fetal cortisol levels to prepartum values in the immature fetus at 128--132 days of gestation reduced placental 11 beta-HSD2 activity to term values. In contrast, 11 beta-HSD2 activity in the fetal renal cortex was unaffected by gestational age or cortisol infusion. When all the data were combined, there was an inverse correlation between the log fetal plasma cortisol level at delivery and placental 11 beta-HSD2 activity, expressed both on a weight-specific basis and per mg placental protein. Fetal cortisol therefore appears to be a physiological regulator of placental, but not renal, 11 beta-HSD2 activity in fetal sheep during late gestation. These findings have important implications, not only for glucocorticoid exposure in utero, but also for the local actions of cortisol within the placental tissues that are involved in initiating parturition in the sheep.

scholarly journals Influence of cortisol on adipose tissue development in the fetal sheep during late gestation

2003 ◽  
Vol 176 (1) ◽  
pp. 23-30 ◽  
Author(s):  
A Mostyn ◽  
S Pearce ◽  
H Budge ◽  
M Elmes ◽  
AJ Forhead ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Gestational Age ◽  
Plasma Cortisol ◽  
Late Gestation ◽  
Protein Abundance ◽  
Tissue Development ◽  
Voltage Dependent Anion Channel ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Adipose Tissue Development

The present study examined the extent to which the late gestation rise in fetal plasma cortisol influenced adipose tIssue development in the fetus. The effect of cortisol on the abundance of adipose tIssue mitochondrial proteins on both the inner (i.e. uncoupling protein (UCP)1) and outer (i.e. voltage-dependent anion channel (VDAC)) mitochondrial membrane, together with the long and short forms of the prolactin receptor (PRLR) protein and leptin mRNA was determined. Perirenal adipose tIssue was sampled from ovine fetuses to which (i) cortisol (2-3 mg/day for 5 days) or saline was infused up to 127-130 days of gestation, and (ii) adrenalectomised and intact controls at between 142 and 145 days of gestation (term=148 days). UCP1 protein abundance was significantly lower in adrenalectomised fetuses compared with age-matched controls, and UCP1 was increased by cortisol infusion and with gestational age. Adrenalectomy reduced the concentration of the long form of PRLR, although this effect was only significant for the highest molecular weight isoform. In contrast, neither the short form of PRLR, VDAC protein abundance or leptin mRNA expression was significantly affected by gestational age or cortisol status. Fetal plasma triiodothyronine concentrations were increased by cortisol and with gestational age, an affect abolished by adrenalectomy. When all treatment groups were combined, both plasma cortisol and triiodothyronine concentrations were positively correlated with UCP1 protein abundance. In conclusion, an intact adrenal is necessary for the late gestation rise in UCP1 protein abundance but cortisol does not appear to have a major stimulatory role in promoting leptin expression in fetal adipose tIssue. It remains to be established whether effects on UCP1 protein are directly regulated by cortisol alone or mediated by other anabolic fetal hormones such as triiodothyronine.

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