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Nuffield Institute for Medical Research, University of Oxford, Headley Way, Oxford, 0X3 9DS
(Received 20 February 1976)
During the latter third of gestation undisturbed foetal sheep with chronically implanted vascular catheters have higher plasma adrenocorticotrophin (ACTH) concentrations than adult sheep (Boddy, Jones, Mantell, Ratcliffe & Robinson, 1974; Jones, Boddy, Robinson & Ratcliffe, 1975a). This is probably the result of a higher rate of secretion from the foetal pituitary (Jones, Luther, Ritchie & Worthington, 1975 b). The plasma glucose concentration of foetal sheep is substantially lower than that of mature sheep (Shelley, 1973). Since hypoglycaemia is a potent stimulus for ACTH secretion (Yalow, Varsano-Aharon, Echemendia & Berson, 1969; Vague, Oliver & Vague, 1972) a correlation between the plasma glucose and ACTH concentrations in pregnant and foetal sheep has been sought.
Plasma samples were collected from 60 pregnant and foetal sheep with chronically implanted carotid arterial catheters as previously described (Boddy et al.
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ABSTRACT
The regulatory factors controlling uterine activity during pregnancy remain unclear in many species. Since myometrial relaxants raise intracellular cyclic AMP, modulation of signalling pathways coupling cell-surface receptors to adenylate cyclase activation could be an important site for control. To assess the functional activity of the stimulatory GTP-binding protein Gs we have measured adenylate cyclase activation by GTP, its non-hydrolysable analogue guanosine 5′-(β-γ-imido)triphosphate (Gpp(NH)p), fluoride, forskolin and manganese in a 50 000 g membrane fraction prepared from the myometrium of non-pregnant, mid-pregnant (30–32 days) and late-pregnant (62–66 days) guinea-pigs (full term 67±2 days). While forskolin- and manganese-dependent enzyme activation was unaltered by pregnancy, maximal stimulation by Gpp(NH)p and fluoride was enhanced by up to 200%. Recovery of adenylate cyclase activity in the 50 000 g fraction was essentially constant at 20–24% of the total activity throughout pregnancy, and thus cannot explain the increases observed. Since guanine nucleotides and fluoride stimulate adenylate cyclase through activating Gs, and forskolin and manganese act at the level of the catalytic unit, these data are consistent with a pregnancy-related increase in Gs functional coupling while adenylate cyclase activity is unaltered. These observations suggest a physiological regulation of myometrial Gs activity during pregnancy which could facilitate hormonal stimulation of adenylate cyclase and contribute to uterine quiescence by increasing uterine sensitivity to relaxants.
Journal of Endocrinology (1990) 127, 15–21
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Nuffield Institute for Medical Research, University of Oxford, Oxford, 0X3 9DS
(Received 11 March 1976)
Vasopressin is considered an important hormone controlling adrenocorticotrophin (ACTH) secretion under some conditions (De Wied, Bohus, Ernst, de Jong, Nieuwenhuizen, Pieper & Yasumura, 1968). Its infusion into dogs at pharmacological but not physiological doses increases plasma ACTH concentration (Andersen & Egdahl, 1964). It behaves as a corticotrophin-releasing factor on incubation with anterior pituitary cells (Portanova, Smith & Sayers, 1970). Moreover a neuroendocrine vasopressin pathway possibly associated with ACTH secretion has been proposed (Parry & Livett, 1973). During hypoxaemia in the foetal sheep there is a rise in both plasma ACTH and vasopressin (Alexander, Britton, Forsling, Nixon & Ratcliffe, 1973; Boddy, Jones, Mantell, Ratcliffe & Robinson, 1974b; Rurak, 1976). Thus the possibility that a rise in foetal plasma vasopressin is responsible for the increased secretion of ACTH during hypoxaemia has been investigated. Foetal and maternal vascular
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SUMMARY
A method is described for the preparation of isotopically pure [3H]oxytocin and [3H]vasopressin from the pooled posterior pituitary glands of groups of four or five rats after the intracisternal injection of [3H]tyrosine. Hormones were separated from deproteinized neurohypophysial extracts by chromatography on Amberlite CG-50, and further purified by chromatography on carboxymethylcellulose. In this way, samples of the hormones were obtained with a very high degree of isotopic purity. The method is suitable for studying the effects of stimuli to the hypothalamo—neurohypophysial system on the biosynthesis and transport of the hormones.
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Nuffield Institute for Medical Research, University of Oxford, Headley Way, Headington, Oxford, 0X3 9DS
(Received 14 September 1976)
It is now well established that corticosteroids can act as negative feedback regulators of adrenocorticotrophin (ACTH) secretion (Yates & Maran, 1974), although unbound steroid is probably much more effective than protein-bound steroid in depressing ACTH secretion (Kawai & Yates, 1966). There are very high plasma corticosteroid concentrations in the foetal sheep during late pregnancy (Bassett & Thorburn, 1969) and although much of this is protein-bound the free corticosteroid concentration is also high (Fairclough & Liggins, 1975). Despite this the plasma ACTH concentration in the foetal sheep at this time is not depressed but may be raised (Rees, Jack, Thomas & Nathanielsz, 1975; Jones, Boddy & Robinson, 1977a). This suggests that the corticosteroids may not act as negative feedback regulators of ACTH secretion in the foetal sheep and the present experiments investigate this
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ABSTRACT
To study the potential role of GH-releasing hormone (GHRH) in maintaining circulating levels of GH during pregnancy, 302 maternal plasma samples were collected from non-fasted subjects at various stages of pregnancy and assayed for GHRH using a 'two-site' immunoradiometric assay. The GH and placental lactogen levels were also determined. In addition, maternal plasma samples taken during labour, amniotic fluid and cord blood were also assayed for these hormones.
Maternal plasma GHRH levels were similar to non-pregnant levels throughout gestation despite fluctuations in GH values which were always higher than non-pregnant levels. There was no significant difference between GHRH levels in maternal plasma and cord blood although high GH levels were observed in the latter. These findings suggest that peripheral GHRH levels do not play an important role in maintaining circulating GH levels during pregnancy.
Journal of Endocrinology (1990) 125, 161–167
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ABSTRACT
Glucocorticoids are known to regulate the contractility of vascular smooth muscle by increasing its response to noradrenaline. The molecular mechanisms for achieving this remain unclear. Recent results in our laboratory have demonstrated that glucocorticoids affect both α1-adrenoceptor number and coupling to G proteins. Whether this leads to an increase in second-messenger production has to be established. The present experiments, therefore, report the effects of dexamethasone on inositol polyphosphate production in vascular smooth muscle cells in culture. Noradrenaline induced the release of inositol polyphosphates from prelabelled [3H]inositol phosphoinositides in the membrane in a dose-dependent manner. The concentration of noradrenaline which caused half-maximal response was 1·26 μmol/l. Prazosin inhibited noradrenaline-induced inositol monophosphate formation to 10·26 ± 3·67% (mean ± s.e.m.; P < 0·01, n = 5) of control value whereas yohimbine reduced it to only 61·74 ± 11·82% (P < 0·05, n = 5), suggesting an action primarily through α1-adrenergic receptors. Dexamethasone (100 nmol/l, 48 h) enhanced noradrenaline-induced inositol monophosphate, bisphosphate and trisphosphate formation up to twofold (P < 0·001, n = 5). The enhancement of the response occurred despite the fact that dexamethasone reduced [3H]inositol prelabelling of membrane phosphoinositides by 49·5 ± 9·9% (P < 0·05, n = 3). The present results suggest that the potential action of glucocorticoids on vascular smooth muscle contractility is, at least in part, through controlling α1-adrenoceptor-mediated second-messenger production.
Journal of Endocrinology (1992) 133, 405–411
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ABSTRACT
Guinea-pig neural lobes contain appreciable amounts of neurophysin with a glycopeptide extension (NPGP) which may represent a partially processed form of the arginine vasopressin (AVP) precursor. We have now studied the turnover and release of the NPGP component using a combination of in-vivo radiolabel incorporation and high pressure liquid chromatography. Measurement of the neural lobe content of 35S-labelled peptides at various times after hypothalamic injection of [35S]cysteine demonstrated that the oxytocin-related products accumulated more rapidly than the AVP-related products. The relative amounts of [35S]cysteine incorporated into NPGP and the AVP-related neurophysin (NPavp) changed markedly with time after in-vivo labelling. In-vitro incubation of neurosecretory granules prepared from neural lobes 4 h after radiolabel injection produced a time- and temperature-dependent conversion of NPGP to NPavp. Incubation at 37 °C for 4 h produced a 30% decrease in [35S]NPGP with a concomitant increase in [35S]NPavp, whilst there were no changes in the other 35S-labelled components. In-vitro stimulation of radiolabelled neural lobes by 56 mm-K+ evoked a Ca++-dependent release of NPGP as well as the other expected neurosecretory components, and the amount of NPGP released reflected its neural lobe content. We conclude that the NPGP component found in guinea-pig neural lobes is a biosynthetic intermediate, most of which is further processed to NPavp. However, some NPGP may also be secreted from the neural lobe in an intact form.
J. Endocr. (1984) 103, 347–354
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ABSTRACT
The possibility that the sensitivity of the adrenal cortex to endogenous ACTH may be affected by splanchnic nerve activity has been investigated in conscious, weaned, 5- to 8-month-old lambs. The animals were atropinized (0·5 mg/kg) and tested with an i.v. infusion of noradrenaline (333 ng/kg per min for 10 min), which produced a significant rise in the mean concentration of both ACTH and cortisol in the arterial plasma. In lambs tested at least 7 days after section of both splanchnic nerves, just below the diaphragm, the rise in plasma ACTH concentration was significantly greater, and that in plasma cortisol significantly less, than in control lambs. The mean plasma ACTH and cortisol concentrations were linearly related to one another in both groups (r = 0·93 and 0·92) but the sensitivity of the adrenal cortex to the steroidogenic action of ACTH appeared to have been roughly halved 1 week after bilateral splanchnic nerve section.
J. Endocr. (1986) 110, 81–85
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SUMMARY
The changes in plasma ACTH concentration of pregnant sheep and their foetuses during the latter half of pregnancy and during labour were studied. Before 140 days of gestation the mean concentration in foetal arterial plasma was 117 ± 19 (s.e.m.) pg/ml which rose to a mean of 286 ± 63 pg/ml. The rise in ACTH occurred at about the same time as, but not before, the rise in corticosteroid concentration in foetal plasma. The maternal plasma ACTH concentration did not change during the latter half of pregnancy and had a mean concentration of 64 ± 9 pg/ml. During labour there was a progressive rise in the ACTH concentration in foetal plasma which was not associated with any corticosteroid changes. Ethanol did not suppress labour but reduced the ACTH concentration in foetal plasma.
