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ABSTRACT
In previous studies, using one particular antibody, immunohistochemical localization of corticotrophin-releasing factor (CRF) in ovine fetal brain was not possible before 90 days of gestation (term is approximately 150 days), although radioimmunoassay of hypothalamic extracts, using a different antibody, had shown CRF to be present from 63 days. The purpose of this study was to use a variety of CRF antibodies in both immunohistochemistry and radioimmunoassay to determine the presence and concentration of the CRF peptide as early in gestation as possible, and to determine whether more than one molecular size of CRF is detectable at any time in gestation. Seven different antibodies were used on hypothalamic tissue or extracts from seven adult sheep and 37 fetuses from 48 to 140 days of gestation. With one ovine CRF antibody (provided by Dr W. Vale, Salk Institute) immunohistochemical detection of CRF-labelled neurones and nerve fibres of the paraventricular nucleus and median eminence was possible from 49 days. The antibody with the greatest sensitivity in radioimmunoassay was one raised against human CRF, Ab-code R1 (provided by Dr E. Hillhouse, University of Newcastle upon Tyne). The hypothalamic contents of CRF (ng/whole hypothalamus) were 0·28±0·06 (mean ± s.e.m.) (n = 4), 9·0±0·6 (n = 5), 14·3±0·6 (n = 5), 30·0±3·4 (n = 4) in fetuses at 48–50, 100–109 and 139–140 days of gestation and in adult sheep respectively. At all ages only one peak of CRF-like activity, which co-eluted with synthetic ovine CRF, was observed after chromatography of hypothalamic extracts, and assays performed with three different antibodies. Thus there are small amounts of CRF in the ovine fetal pituitary from very early in gestation (50 days), and there is no evidence for a larger molecular weight form, as seen in the immature human fetus.
Journal of Endocrinology (1991) 129, 335–341
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ABSTRACT
Cortisol was infused, intravenously, for 4 h continuously into 5 chronically cannulated ovine fetuses at 111-120 days of gestation (term is 142-152 days). The dose used was 100 μg/h, and raised fetal blood cortisol concentrations from 8.2±4.0 to 56.5±19.0 nmol/l (values are mean ± SEM). The effects observed were 1) a 4-5 fold increase in sodium and chloride excretion, 2) a doubling of potassium excretion and free water clearance, 3) no significant changes in urine pH, urea and creatinine excretions, and 4) an increase in urine osmolality from 129±7.5 to 154.4±11.3 mosmol/kg water. There were no significant changes in any of the measured parameters in 5 fetuses infused with 0.9% NaCl for 4 h. It is suggested that the hyponatremia and inability to retain sodium observed in many premature or very low birth weight babies may be due to the fact that their kidneys are behaving as fetal rather than neonatal organs and responding to the high plasma cortisol concentrations found in such babies with a natriuresis.
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ABSTRACT
The ability of opioid peptides to affect plasma immunoreactive ACTH concentrations was examined in conscious sheep. Plasma concentrations of ACTH were significantly increased by an i.v. infusion of Met-enkephalin and its analogue (FK-33824). There was a dose-dependent increase in plasma concentrations of ACTH with a graded administration of FK-33824. The combined effect of Met-enkephalin and ovine corticotrophin-releasing factor (oCRF) or FK-33824 and oCRF on plasma concentrations of ACTH was greater than the effect of each peptide when given individually. This study demonstrates that Met-enkephalin and its analogue stimulate ACTH release in sheep.
J. Endocr. (1986) 111, 463–467
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ABSTRACT
The switch from γ (fetal) to β (adult) globin production was studied by the analysis of globin synthesis in chronically cannulated ovine fetuses and newborn lambs. The γ/α globin synthesis ratio decreased from 0·98 ± 0·11 (s.d.) (n = 4 samples) at 100–120 days of gestation to 0·15± 0·07 (n = 4) in lambs of 150–156 days post-conception, and the β/α synthesis ratio increased from 0·04 ± 0·06 (n = 4) to 1·13 ± 0·21 (n = 4) over the same period. In bilaterally adrenalectomized fetuses, which survived in utero until 151–156 days, the γ/α and β/α synthesis ratios were 0·64 ± 0·14 (n = 3) and 0·25 ± 0·07 (n = 3) respectively in the 150- to 156-day period. Bilateral adrenalectomy did not affect the time of onset of β globin synthesis, but significantly decreased the rate. In one bilaterally adrenalectomized fetus the infusion of increasing concentrations of cortisol restored the rate of β globin synthesis to normal. Treatment of three intact fetuses with 100 μg cortisol/h for 3 weeks, from 100 to 121 days, did not affect the timing or rate of switch from γ to β globin synthesis. Thus fetal adrenal secretions, probably cortisol, affected the rate of change of γ to β globin synthesis but other factors must have been involved in the initiation of the switch.
J. Endocr. (1985) 104, 165–170
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Abstract
Pituitary-adrenal responses to intravenous infusion of ovine corticotrophin-releasing hormone (oCRH) or arginine vasopressin (AVP) and to haemorrhage were examined in the ovine foetus prior to 90 days of gestation (term 145–150 days). In chronically cannulated foetuses (n=8), between 74 and 84 days of gestation, basal ACTH levels were less than 20 pg/ml while cortisol levels were 6·5 ± 1·5 nmol/l (mean±s.e m.). Intravenous infusion of oCRH (1 μg/h for 60 min) or AVP (1 μg/h for 60 min) significantly increased ACTH (P<0·05 for both treatments) and cortisol (P<0·01 for both treatments) levels, although the response to both hormones was modest. In acutely studied foetuses of a similar age (70–90 days of gestation, mean 82·0 ± 1·4 days, n=7), exteriorization and progressive haemorrhage significantly (P<0·05) elevated ACTH levels from 117·4 ± 32·1 pg/ml to a maximal value of 329·2 ± 112·8 pg/ml, the maximal ACTH response corresponding to the removal of a volume of blood equivalent to 6·6 ±1·2% of the pre-haemorrhage body weight. The present study has demonstrated that the ovine foetal pituitary, in vivo, is responsive to exogenous and endogenous stimuli by mid-gestation and, at this age, although basal cortisol levels are low, the foetal adrenal is capable of responding to elevated ACTH levels in the short term.
Journal of Endocrinology (1995) 145, 455–460
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ABSTRACT
During pregnancy, in women and the rat, there is a resetting of the plasma osmolality–arginine vasopressin relationship (Posmol/PAVP) such that a decrease in Posmol is maintained without suppression of PAVP. This occurs at a time when relaxin is detectable in plasma. The hypothesis tested here was that relaxin could alter the Posmol/PAVP in the non-pregnant rat. One group of ovariectomized rats (n = 15) was treated for 7 days with intravenous synthetic human relaxin (10 μg/h) in 10 pi 0·9% (w/v) NaCl. Controls were two groups of rats either with no treatment (n = 15) or treated with vehicle alone (n = 15). One-third of each group received hypertonic saline (0·4 mol NaCl/l, 2 ml/100 g body weight i.p.) on day 7, and one-third were deprived of water for the final 24 h. All rats were killed by decapitation and blood was collected rapidly (<40 s) for hormone and osmolality assays. The Posmol in all relaxin-treated rats was significantly (P < 0·001) lower than that in both control groups, but the PAVP was unchanged. The log PAVP/Posmol regression line was significantly shifted in elevation (P <0·001) but not in slope. Thus treatment of ovariectomized rats with relaxin caused changes in fluid balance which mimic those occurring in normal pregnancy.
Journal of Endocrinology (1993) 137, 505–510
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ABSTRACT
This study was designed to investigate the effects of pulsatile infusion of ACTH into ovine fetuses on the endocrine changes that precede parturition, the timing of birth and the subsequent survival of the lamb. Where appropriate, these parameters were compared with fetuses infused with pulses of saline and uninfused normal term fetuses. Ten fetuses received a 15-min infusion of synthetic ACTH(1–24) (79 ng/min) from day 125 (n=9) or day 126 (n=1) of gestation. Seven fetuses were born prematurely within 174±14 h (mean ± s.e.m.) after the commencement of the infusion, i.e. at 132 ± 0·6 days, whilst three died in utero at 130–131 days. When born all lambs could breath, walk and suckle. Of the seven premature lambs, four died 2–10 days after parturition but three survived for at least 12 months after birth. Fetuses infused with pulses of ACTH exhibited intermittent but very large increases in plasma ACTH values, with the first pulse, on day 1, increasing ACTH values from 5·1 ± 1·1 to 140 ± 31·3 pmol/l (P<0·001). At the next sampling time, ACTH values were not significantly different from preinfusion values. A similar plasma ACTH profile was observed on each subsequent day of ACTH treatment. In contrast, fetuses (n=4) infused with pulses of saline between 125 and 131 days exhibited fetal plasma concentrations of ACTH which ranged between 2 and 12 pmol/l for the majority of the time. Of the uninfused fetuses (n=8) that were studied during the last week of normal gestation, seven were born alive at 148·9± 1·0 days of gestation, whilst one lamb was stillborn at 146 days. In these fetuses, plasma concentrations of ACTH increased slowly to 35·6 ±2·4 pmol/l on the day before delivery with a further increase to 76·4± 3·9 pmol/l occurring on the day of delivery. In fetuses infused with pulses of ACTH there was also a significant (P< 0·001) increase in the fetal cortisol to corticosterone ratio from a value of 2·9 before the commencement of the infusion to 69·1 just before birth. In ewes bearing uninfused fetuses born at normal term, maternal plasma concentrations of progesterone on day 4 before delivery were significantly (P<0·05) lower than on day 5 before delivery. In comparison, in ewes bearing fetuses infused with pulses of ACTH, a significant (P<0·05) decrease from maternal plasma concentrations of progesterone on day 5 before delivery did not occur until day 1 before delivery. In ewes bearing uninfused or prematurely delivered fetuses infused with pulses of ACTH, maternal plasma concentrations of oestrogen did not significantly (P<0·01) increase until the day of parturition. It is concluded that a minimum of 6–7 days of ACTH treatment is required by the fetal adrenal for the induction of cortisol synthesis sufficient to produce the birth of viable lambs. However, premature lambs have a 57% mortality rate in the 2- to 10-day period after birth.
Journal of Endocrinology (1990) 124, 99–107
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ABSTRACT
Effects of maternal sodium depletion on the composition of ovine fetal fluids were studied. Maternal Na depletion was achieved by 48-h drainage of parotid saliva. There was a significant decrease in both maternal and fetal plasma Na concentration, indicating that both mother and fetus had experienced the Na-depletion stimulus. There was a significant increase in maternal blood aldosterone but the change in fetal blood aldosterone was not significant. In animals where there was an increase in fetal blood aldosterone the increase could be accounted for by transfer of aldosterone across the placenta from the mother. There was a significant decrease in fetal urinary Na concentration and Na excretion and the urinary Na/K ratio fell in seven out of eight studies. These observations are consistent with the hypothesis that fetal Na depletion sensitizes the fetal kidney to the action of circulating aldosterone as in the adult.
J. Endocr. (1985) 107, 177–182
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The blood clearance rate (BCR) of cortisol was measured in non-pregnant ewes and in pregnant ewes and their intact or bilaterally adrenalectomized fetuses. In pregnant sheep the placental transfer of cortisol in both directions was established. The BCR of cortisol in the non-pregnant sheep was 51·7±4·9 (s.e.m.)1/h (n = 36) or 1·151/h per kg body weight. This was lower than that in the pregnant ewe (97–143 days of gestation) of 76·9±4·21/h (n = 9) or 1·851/h per kg.
In the intact fetus the BCR was 8·2±0·261/h (n = 10) over the same period of gestation. The percentage of the maternal production rate of cortisol transferred to the fetus was 1·4±0·11% (n = 9) and the placental transfer from fetus to mother was 19·5±1·5% (n = 8). The BCR in pregnant ewes bearing bilaterally adrenalectomized fetuses was not significantly different from that of mothers of intact fetuses (58·4±7·71/h; n = 6). The BCR of adrenalectomized fetuses was 8·4±1·371/h (n = 8). The placental transfer of cortisol from mother to fetus was sufficient to account for all the cortisol measured in adrenalectomized fetuses and in intact fetuses of 100–121 days of gestation. However, it accounted for only 37% of the cortisol measured in fetuses of 122–135 days of gestation and 12% or less in fetuses older than 136 days of gestation.
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To determine the percentage of the maternal secretion of aldosterone which crosses the placenta the blood clearance rate (BCR) of aldosterone was measured in pregnant sheep and in chronically cannulated fetuses by the constant infusion of [3H]aldosterone alternately into the maternal and fetal compartments. When equilibrium had been reached the concentration of [3H]aldosterone was measured in both maternal and fetal compartments. Aldosterone BCR in eight pregnant ewes was 98 ± 5 (s.e.m.) litres/h which was not significantly different from that of ten non-pregnant ewes at 95 ± 5 litres/h. The BCR of aldosterone in seven fetuses was 24 ± 2 litres/h. A small percentage (4·4 ± 0·3; n = 7) of the maternal production rate was transferred to the fetus, whilst 29 ± 4% (n = 8) of the fetal production rate was transferred to the maternal compartment.
When aldosterone was measured in maternal and fetal blood samples collected simultaneously from sodium-replete sheep more than 80% of the aldosterone in fetal blood was of fetal origin if the actual fetal concentration of aldosterone was greater than 1·5 ng/dl.
