Endothelin stimulates ACTH secretion in the ovine fetus

The endothelins are a series of peptides with potent vasoconstrictor effects in vascular tissue; however, they may also have a role as neuroendocrine secretagogues because endothelin and endothelin receptors have been found in hypothalamic and pituitary tissues. Since activation of the fetal hypothalamo-pituitary-adrenal axis is crucial to the process of parturition, the aim of this study was to determine whether endothelin could activate the hypothalamo-pituitary-adrenal axis in the ovine fetus. Catheters were inserted into the carotid artery, jugular vein and lateral cerebral ventricle of six fetal lambs at 118-122 days' gestation. After a 5-day recovery period, endothelin-3 or placebo (saline) was infused intravenously (i.v.) or intracerebroventricularly (i.c.v.) over 30-60 min. The dose of endothelin-3 employed was 0.01 and 0.1 microgram min-1 i.c.v. and 0.1 and 1.0 microgram min-1 i.v. Arterial blood was taken from the fetus before, during and for 1 h after the infusion for measurement of ACTH and cortisol. Blood gas analysis was also performed. Intravenous endothelin-3 produced a dose-dependent increase in ACTH and cortisol concentrations in fetal plasma and was associated with transient fetal hypoxia and acidosis. pH correlated inversely with plasma ACTH (r = -0.701, P < 0.001) and cortisol (r = -0.308, P < 0.001) concentration. An increase in ACTH and cortisol concentrations in fetal plasma was also induced by endothelin-3 administered i.c.v. at 0.1 microgram min-1, and this was not associated with fetal acidosis These data suggest that endothelin administered i.v. will stimulate ACTH and cortisol release indirectly through vasoconstriction and acidosis; however, the response to i.c.v. endothelin administration suggests that it may also act as a central secretagogue for ACTH in the fetus and could therefore play a role in the process of parturition.