Endothelin-1 Stimulates the in vitro Release of Neurohypophyseal Hormones, but Not Corticotropin-Releasing Hormone, via ET_A Receptors

Abstract

The endothelins consist of a family of vasoconstrictor peptides originally isolated from endothelial tissue which are now known to be involved in neuroendocrine regulation. However, while there are data indicating the involvement of endothelins in the modulation of the hypothalamo-pituitary-adrenal (HPA) axis, the precise mechanisms involved have been unclear. We have therefore used a previously validated rat hypothalamic explant system in order to investigate the possible modulation of the neurohypophyseal hormones vasopressin and oxytocin, and corticotropin-releasing hormone (CRH), by endothelin-1 (ET-1) and endothelin-3 (ET-3). Following a period of stabilisation, the release of vasopressin, oxytocin and CRH remained approximately constant in successive 20-min incubations. Addition of ET-1 stimulated the release of vasopressin at a dose of 0.1 nmol/l (p < 0.05), and both vasopressin and oxytocin at 10 nmol/l (p < 0.01 and 0.05, respectively). The release of vasopressin and oxytocin induced by 10 nmol/l ET-1 were both totally blocked by co-incubation with either 1 or 10 µmol/l of the specific ET_A receptor subtype antagonist cyclo (D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123). ET-1 had no effect on CRH release in the dose range of 0.1-1,000 nmol/l. In case any possible stimulation of CRH might be masked by simultaneous generation of nitric oxide (NO), an inhibitor of CRH secretion, addition of ET-1 was also carried out in the presence of the NO synthase inhibitor, L-NO-Arg: ET-1 was again without effect in this dose range. ET-3 had no effect on any hormone at any concentration. It is concluded that ET-1 may be involved in the control of both vasopressin and oxytocin secretion, most probably at receptors relatively unresponsive to ET-3, the ET_A recpetor. Any direct effect of the endothelins on the HPA axis is likely to be exerted via hypothalamic vasopressin rather than CRH.

Review: Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal axis

“…Increasing substrate levels for haem oxygenase inhibited IL-1-stimulated production of CRH and AVP (Pozzoli et al 1994), an effect that was reversed by inhibition of haem oxygenase activity, while a haem analogue exerted a stimulatory effect on CRH release (Parkes et al 1994). NO and CO selectively modulate the release of CRH and AVP from rat hypothalami in response to lipopolysaccharide (Kostoglou-Athanassiou et al 1998), providing evidence for a counter-regulatory mechanism controlling the HPA axis response to immune activation.…”

“…Overall, there is no convincing evidence for a specific role for ET-1 in regulating the HPA axis. ET-1 stimulated the basal release of AVP from rat hypothalami in vitro (Shichiri et al 1989, Yasin et al 1994, but this is likely to be from magnocellular neurons which mediate the neurohypophysial response to alterations in blood pressure.…”

“…ET-1, the principal mammalian form, did not affect basal release of CRH from rat hypothalamic explants (Yasin et al 1994) and had no effect upon potassium-stimulated CRH release from rat hypothalami, but did inhibit CRH-induced ACTH release from pituitary cell cultures (Calogero et al 1994). In contrast with these inhibitory effects, ET-1 stimulated basal ACTH secretion in rats (Calogero et al 1994, Malendowicz et al 1997.…”

Nitric oxide modulation of ETB receptor-induced vasopressin release by rat and mouse hypothalamo-neurohypophyseal explants

“…Notably, pharmacological inhibition of NOS is frequently associated with a concurrent increase in arterial pressure that may suppress AVP release via baroreflex mechanisms, thereby masking an effect by nitric oxide (27,29). Although the mechanism of interaction of ET, AVP, and nitric oxide has been studied in several other tissues (10,19,44), the direct effect of nitric oxide on ET B receptor-induced AVP secretion has not been studied.…”

Endothelin-1 induces lipolysis in 3T3-L1 adipocytes

“…Through these complex signaling systems, ET-1 evokes a diverse range of biological responses, including bronchoconstriction (13), vasoconstriction (46), cell proliferation (12,26), and modulation of hormone and neurotransmitter release (34,48).…”