Modulation of ET_B receptor-induced arginine-vasopressin secretion by N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid (GABA)-dependent mechanisms in hypothalamo-neurohypophysial explants

The endothelins (ETs) stimulate the secretion of arginine-vasopressin (AVP) in vivo and in vitro. The activation of hypothalamic ET_B receptors increases AVP release, but the neurotransmitters mediating these responses are not known. In the compartmentalized hypothalamo–neurohypophysial explant model, the overall basal release of AVP was 53±17pg·h^-1·PP^-1 (where PP is posterior pituitary). ET_B receptor activation in hypothalamic sites by 1nM IRL1620 dose-dependently increased AVP secretion, with a maximal response of 340±70% of basal·h^-1·PP^-1, whereas 1nM ET-1, the ET_A receptor-selective agonist, inhibited AVP release to 44±8%·h^-1·PP^-1. Addition of MK801 along with IRL1620 inhibited AVP release to a value no different from basal (122±41%·h^-1·PP^-1). In contrast, 10µM DNQX [6,7-dinitroquinozaline-2,3-(1H,4H)-dione] did not block ET_B receptor-induced AVP release (326±73%·h^-1·PP^-1), and nor did non-selective α-adrenergic receptor antagonism. The GABA_A (where GABA is γ-aminobutyric acid) receptor agonist muscimol (10µM) inhibited AVP release in response to IRL1620 (127±30%·h^-1·explant^-1). These data suggest that AVP release induced by activation of hypothalamic ET_B receptors is mediated by a hypothalamic N-methyl-D-aspartate (NMDA) receptor-mediated mechanism. In turn, the local release of GABA associated with NMDA activation may exert an inhibitory influence and dampen the AVP secretory response.