The endothelins (ET) have been implicated in vasopressin (AVP) release in vivo and in vitro. The effects of ET in this system are complex, and the net AVP secretory response likely depends upon a unique combination of ET isoform, ET receptor subtype and neural locus. The purpose of these studies was to examine the role of ET receptor subtypes at hypothalamic vs neurohypophysial sites on somatodendritic and neurohypophysial AVP secretion. Experiments were done in cultured explants of the hypothalamo-neurohypophysial system of Long Evans rats. Either the whole explant (standard) or only the hypothalamus or posterior pituitary (compartmentalized) was exposed to log dose increases (0.01-10 nM) of the agonists ET-1 (ET_A selective) , ET-3 (non-selective), or IRL1620 (ET_B selective) with or without selective ET_A (BQ123, 2-200 nM) or ET_B (IRL1038, 6-600 nM) receptor antagonism. In standard explants, ET-1 and ET-3 dose dependently increased whereas IRL1620 decreased net AVP release. Hypothalamic ET_B receptor activation increased both somatodendritic and neurohypophysial AVP release. At least one intervening synapse was involved as tetrodotoxin blocked the response. Activation of ET_A receptors at the hypothalamic level inhibited, whereas ET_A receptor activation at the posterior pituitary stimulated neurohypophysial AVP secretion. Antagonism of hypothalamic ET_A receptors potentiated the stimulatory effect of ET-1 and ET-3 on neurohypophysial secretion, an effect not observed with ET_B receptor-induced somatodendritic release of AVP. Thus, the response of whole explants reflects the net result of both stimulatory and inhibitory inputs. The integration of these excitatory and inhibitory inputs endows the vasopressinergic system with greater plasticity in its response to physiologic and pathophysiologic states.