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Xiaoming Wang, Janette J. Tresham, Mario Congiu, Bruce A. Scoggins and John P. Coghlan

Abstract. The role of opioids in the regulation of arginine vasopressin release from the posterior pituitary is a subject of controversy. In the present study, we examined the effects of central administration of met-enkephalin, leu-enkephalin, the enkephalin analogue FK-33824, and the opiate antagonist naloxone, and the effects of systemic administration of met-enkephalin and FK-33824 on AVP secretion in conscious normal sheep. Intracerebroventricular infusion of FK-33824 significantly increased the plasma concentration of immunore-active AVP in a dose-dependent manner, but met-enkephalin, leu-enkephalin and naloxone failed to change plasma concentration of AVP. Intravenous infusion of met-enkephalin and FK-33824 also failed to change plasma concentration of AVP. The opiate antagonist naloxone given both centrally and systemically attenuated the increase in plasma concentration of AVP induced by FK-33824. We conclude that basal AVP release is stimulated by central administration of FK-33824.

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Kathy Tangalakis, John P. Coghlan, Robert Crawford, Vicki E. Hammond and E. Marelyn Wintour

Abstract.

Between 90 and 120 days of gestation (term = 147±5), when plasma cortisol concentrations in the fetus are at a minimum, levels of mRNA encoding the steroidogenic enzymes 17α-hydroxylase (P-45017α) and cholesterol side-chain cleavage (P-450scc) are also very low. Over the following 30 days, P-45017α and P-450scc gene expression increases concurrent with increasing fetal cortisol concentration. The hypothesis tested in this study was that cortisol biosynthesis is minimal in the period 90-120 days because of insufficient ACTH. Fetuses were cannulated between 98-102 days of gestation. Following recovery, 7 fetuses received 24-h ACTH infusions (12 μg/24 h) and 5 fetuses received 24-h vehicle infusions; 4 ACTH-infused and 4 vehicle-infused fetuses were then sacrificed immediately after cessation of the infusion. The other fetuses were left in utero for 3 days prior to sacrifice. Fetal blood samples were analysed for ACTH and cortisol and the adrenals processed for hybridization histochemistry and Northern blot analysis. ACTH, but not vehicle, induced significant increases in the width of the adrenal cortex and in the levels of P-45017α and P-450scc mRNA. Concurrently, fetal plasma ACTH and cortisol concentrations also increased significantly. In adrenals from fetuses left in utero for 3 days after cessation of the ACTH infusion, P-45017α and P-450scc mRNA levels returned to control levels. Plasma ACTH and cortisol levels also approximated basal values. P-450c21 mRNA levels did not vary significantly at any time with the treatments. It can be concluded that the major regulatory influence on ACTH in the 90-120 day fetus is via increased gene expression of P-45017α and P-450scc but not P-450c21.

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Suzanne F. Abraham, John R. Blair-West, John P. Coghlan, Derek A. Denton, David R. Mouw and Bruce A. Scoggins

ABSTRACT

Conscious sheep with permanent indwelling cannulae in the lateral ventricles and the cisterna magna were Na depleted and then perfused for 9 h with an artificial CSF solution. There were 3 experimental groups: Group I (n = 5) received perfusion with artificial CSF containing Na 170 mEq./l, Group II (n=7) received perfusion with artificial CSF containing Na 145 mEq./l, Group III (n = 7) received no perfusion. In Group I the blood aldosterone level fell from 26.4 ± 7.4 to 8.6 ± 2.3 ng/100 ml by 9 h after perfusion. There was no significant change in plasma [Na] or [K], blood angiotensin II or plasma renin concentration. Blood cortisol and corticosterone levels rose. There was also a fall in blood aldosterone in Group II but this was not significant until 4 h post-perfusion. Group III showed no significant change in blood aldosterone concentration. Multivariate statistical analysis showed that the fall in aldosterone levels during 170 mEq./l Na perfusion could not be accounted for by changes, either alone or together, of ACTH as evidenced by alteration in blood cortisol or corticosterone, or by change of plasma [Na], [K] or renin concentrations. This data supports the hypothesis of an additional factor which may be of CNS origin being involved in the control of aldosterone secretion.

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Eric H. Mills, John P. Coghlan, Derek A. Denton, Campbell D. Spence, Judith A. Whitworth and Bruce A. Scoggins

Abstract. Glucocorticoid induced hypertension has been regarded as independent of sodium (Na), in contrast to mineralocorticoid induced hypertension, which is Na+-dependent. These studies compare the effect of Na+ depletion and potassium (K+) loading on glucocorticoid hypertension induced by cortisol in conscious sheep. Cortisol (480 mg/d) for 5 days, in sheep on a normal chaff diet (90–140 mmol/d Na+, 200–250 mmol/d K+) increased mean arterial pressure by 18 mmHg on day 5, increased plasma Na+ concentration, reduced plasma K+ concentration, and did not change urinary Na+ excretion. Following Na+ depletion (Na+ loss 603 ± 49 mmol), cortisol increased mean arterial pressure from 70 ± 1 mmHg to 76 ± 3 mmHg on day 5 (P < 0.001) and the increase in pressure was significantly less than the increase seen on the normal diet (P < 0.05). Plasma Na+ increased and plasma K+ decreased. Urinary Na+ and K+ excretion was unchanged. KCl loading (700–900 mmol/day) for 10 days had no effect on the maximum rise in mean arterial pressure (+18 mmHg with cortisol in K+ loaded sheep). Plasma Na+ and K+ fell, and urinary Na+ excretion increased during the infusion. These studies show that Na+ depletion, but not KCl loading, reduced cortisol induced hypertension in sheep. These data show that glucocorticoid hypertension is not independent of Na+ status.

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Kathy Tangalakis, John P. Coghlan, John Connell, Robert Crawford, Paula Darling, Vicki E. Hammond, Jim Haralambidis, Jenny Penschow and E. Marelyn Wintour

Abstract. Northern blotting and hybridization histochemistry were used to evaluate the ontogeny and cellular distribution of the mRNAs of the cytochrome P-450 enzymes: cholesterol side-chain cleavage (P-450scc), 17α-hydroxylase (P-45017α) and 21-hydroxylase (P-450c21) in 40 ovine fetal adrenals from 42 days of gestation until term (151 days). The genes for P-45017α and P-450scc were expressed strongly in tissue from young (40–60 days) and old fetuses (120 days to term), but to a very minor degree in 90–120 day fetuses. P-450c21 showed a steady increase throughout gestation. In the morphologically immature an unzoned adrenal of the 40-50 day fetus there was some differentiation in gene expression, all cells containing P-450scc and P-450c21 but a few lacking P-45017α. Once morphological zonation had occurred (80 days), P-45017α was confined to the fasciculata. After 120 days there was a radial maturation pattern of the fasciculata cells morphologically, adult-type cells first appearing at the medullary border. However, P-45017α and P-450scc mRNAs were equally well expressed in all sections of the fasciculata. The conclusions were: 1) the previously demonstrated triphasic cortisol biosynthetic capacity of ovine fetal adrenals was correlated with the presence, absence, and reappearance of mRNAs P-45017α and P-450scc; 2) morphological appearance of fetal adrenocortical cells and expression of three major steroidogenic enzyme genes were not correlated.

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John G. McDougal, Aldona Butkus, John P. Coghlan, Derek A. Denton, Jürg Müller, CatherineJ. Oddie, Peter M. Robinson and Bruce A. Scoggins

Abstract.

The effect of ACTH administration for 1—5 days on the morphology and steroidogenic capability of sheep adrenal tissue has been examined. During this period of treatment there was a gradual decline in the in vitro conversion of 3H-labelled precursors to products of solely zona glomerulosa origin (aldosterone and 18-hydroxycorticosterone) while conversion to products of zona fasciculata origin (17-hydroxyprogesterone, 11-deoxycortisol and cortisol) was stimulated throughout. Conversion to DOC, 18-hydroxydeoxycorticosterone and corticosterone (steroids produced by both the zona glomerulosa and the zona fasciculata) declined after initial stimulation.

Within 2—3 days of the commencement of treatment, the zona glomerulosa showed a progressive decrease in cell number associated with disruption of cords and cell separation. Ultrastructurally, it was found that typical zona glomerulosa cells had almost disappeared. The majority of residual cells in this area had a structure intermediate between zona glomerulosa and zona fasciculata cells.

The similarity in time-course of the alterations in both the morphological and biosynthetic characteristics suggests that the decline in aldosterone output caused by ACTH administration to sheep results from the loss of adrenal zona glomerulosa cells, predominantly due to selective cellular degeneration.