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In the sheep fetus, plasma levels of gastrin are raised above adult levels from 2 weeks before birth. This observation initiated the present study on the maternal and fetal secretion rate, metabolism and placental transfer of gastrin. The experiments were performed on conscious pregnant ewes with chronically cannulated fetuses and on newborn lambs. Metabolic clearance rate (MCR), production rate (PR) and placental transfer of gastrin were measured by alternate steady-state infusion of gastrin into the mother and fetus. Plasma levels of gastrin were measured by radioimmunoassay.
Metabolic clearance rate was similar in the pregnant and non-pregnant ewe (8·4± 1·1 (s.e.m.) and 9·0±1·4 ml/min per kg) respectively. However, fetal MCR was significantly increased. Term was 145 days. Metabolic clearance rate was 15·5 ± 1·7 at 110–125 days of gestation, 25·6 ± 2·9 at 126–135 days, 29·7 ± 4·9 at 136–145 days and remained raised in the first 2 weeks post partum.
Gastrin did not cross the placenta in either direction. Placental destruction of gastrin was not responsible for the increased fetal MCR as umbilical artery and umbilical vein levels were not significantly different during fetal gastrin infusion. Furthermore, MCR remained raised in the newborn lambs. Gastrin PR was significantly increased at all ages.
The results showed that the previously reported fetal hypergastrinaemia is from fetal sources and is not a result of immaturity of clearance mechanisms. In fact, fetal MCR was significantly increased. The increased fetal plasma gastrin levels are due to an increased rate of production from the fetus.
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ABSTRACT
Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism.
The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain.
The metabolic clearance rate at steady state was 22·6 ± 2·1 (s.e.m.) and 15·0±1·7 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3·6±0·3 min for the first phase and 13·6±1·0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1–37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial–renal vein gradient of 14%, and the liver, with a portal– hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP. The specific organ clearance, however, accounted for only one-third of the whole body metabolic clearance rate of CGRP, suggesting that other more generalized degradative systems are involved, such as endothelial-bound enzymes of blood vessels. This information on clearance and organ-specific metabolism should form a basis for evaluating the physiological roles and modes of action of CGRP.
J. Endocr. (1988) 118,25–31
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* Department of Physiology, University of Melbourne, Parkville, Victoria 3052, Australia, † Department of Surgery, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia, and ‡ Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria 3052, Australia
(Received 19 October 1977)
Aldosterone is present in the peripheral blood of ovine foetuses from at least 60 days until term at 147 ± 5 days (Wintour, Brown, Denton, Hardy, McDougall, Oddie & Whipp, 1975). To determine the biological significance of this steroid in the foetus, infusions of aldosterone were made into foetuses bearing chronic vascular and bladder cannulae and the urinary sodium: potassium Na+: K+) ratio was measured before, during and after infusion. Silastic cannulae (0·76 mm internal diameter, 1·65 mm outer diameter) were placed 6–8 cm into the left carotid arteries and right jugular veins of seven ovine foetuses between 86 and 120 days of gestation and a
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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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ABSTRACT
Intact and hypophysectomized freshwater (FW) silver eels were transferred to tanks of FW or artificial sea water (SW; salinity = 0·60 osmol/l) which were simultaneously renewed twice a week. Fish were killed 2 months after transfer and plasma was assayed for ovarian steroids.
In all fish, 5α-androstane-3β,17β-diol was present, while 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol were undetectable.
In intact FW eels, plasma levels of testosterone, 5α-androstane-3β,17β-diol and oestradiol-17β were approximately 0·15 nmol/l. In intact SW eels, no change in plasma levels of testosterone and 5α-androstane-3β,17β-diol was found, whereas the concentration of oestradiol-17β was increased significantly (P<0·01), indicating stimulation of aromatase activity.
In hypophysectomized compared with intact FW fish, plasma levels of testosterone and 5α-androstane-3β,17β-diol were decreased (P<0·05) and there was a slight but significant (P<0·01) augmentation of the plasma concentration of oestradiol-17β which may have involved the removal of pituitary-dependent inhibition of aromatase activity, possibly by 5α-reduced compounds.
In hypophysectomized compared with intact SW fish, plasma levels of testosterone, 5α-androstane-3β,17β-diol and oestradiol-17β were decreased (P<0·05); in the case of oestradiol-17β, this may have reflected the diminished ovarian synthesis of testosterone, its precursor. The plasma level of oestradiol-17β was, however, higher in SW than in FW fish, even in hypophysectomized eels. This suggests that extra-pituitary mechanisms mediate, at least partly, the effects of transfer to SW on aromatase activity.
J. Endocr. (1987) 114, 289–294
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Comparisons of aldosterone responses to [des-Asp1]-angiotensin II and angiotensin II, often at single dose levels, have shown a wide range of potency ratios. Therefore four-point dose–response comparisons were performed in sodium-replete sheep, using i.v. infusion rates of angiotension II and angiotensin II amide that reproduced the physiological range of blood concentration of angiotensin II for sheep. Angiotensin III was infused i.v. at the same rates. Effects on arterial blood pressure, cortisol secretion rate, adrenal blood flow and plasma levels of Na+ and K+ were also compared. The potency ratio, angiotensin III: angiotensin II amide, was 0·87 for actual aldosterone secretion rate and 0·90 for the calculated increase in aldosterone secretion. For angiotensin III: angiotensin II the ratios were 0·80 and 0·91 respectively. These ratios were not significantly different from 1·00 but the tendency for angiotensin II to be slightly more potent was probably due to a contribution from derived angiotensin III during infusion of angiotensin II. Angiotensin II or angiotensin II amide was ∼ four times as potent as angiotensin III in raising arterial blood pressure. Cortisol secretion rate was slightly but significantly increased by all peptides at the higher infusion rates. Infusions had no effect on adrenal blood flow or plasma levels of Na + but raised plasma levels of K + slightly. These results confirm the conclusion from adrenal arterial infusion experiments that angiotensin II and III are almost equipotent in stimulating aldosterone secretion in sheep.
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Metoclopramide (10 mg i.v. injection followed by 10 mg/h i.v. for 2 h) caused a transient rise in blood concentrations of aldosterone in sodium-replete and sodium-depleted sheep. Infusion of metoclopramide into the adrenal artery of sheep with an autotransplanted adrenal gland, at a rate to give a similar concentration of metoclopramide at the adrenal cell level (calculated from rate of infusion and adrenal blood flow), resulted in no alteration in aldosterone secretion rate in either sodium-replete or sodium-depleted animals, even though intravenous metoclopramide caused transient stimulation of aldosterone secretion in the same sheep when sodium replete.
Dopamine administered either into the adrenal arterial blood supply or intravenously had no significant effect on aldosterone secretion and did not reverse the stimulatory effects of angiotensin II on aldosterone secretion in the adrenal transplant.
The data do not support the suggestion that direct dopaminergic elements play a tonic inhibitory role in aldosterone secretion. It is possible that the agonist effect of metoclopramide on aldosterone secretion may occur by some non-dopaminergic mechanism and it is tempting to speculate that the effect is centrally mediated.
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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.