Regulation of vasopressin secretion by ET_A and ET_B receptors in compartmentalized rat hypothalamo-neurohypophysial explants

Abstract

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 on 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 (ETA selective), ET-3 (nonselective), or IRL-1620 (ETB selective) with or without selective ETA (BQ-123, 2-200 nM) or ETB (IRL-1038, 6-600 nM) receptor antagonism. In standard explants, ET-1 and ET-3 dose-dependently increased, whereas IRL-1620 decreased net AVP release. Hypothalamic ETB receptor activation increased both somatodendritic and neurohypophysial AVP release. At least one intervening synapse was involved, as tetrodotoxin blocked the response. Activation of ETA receptors at the hypothalamic level inhibited, whereas ETA receptor activation at the posterior pituitary stimulated, neurohypophysial AVP secretion. Antagonism of hypothalamic ETA receptors potentiated the stimulatory effect of ET-1 and ET-3 on neurohypophysial secretion, an effect not observed with ETB 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 physiological and pathophysiological states.anteroventral third ventricle; posterior pituitary; supraoptic nucleus ENDOTHELINS (ET) not only exert powerful direct vasoactive effects but can act as neurotransmitters within the central nervous system (4, 10, 15). Specifically, ET peptides have been implicated in the regulation of vasopressin (AVP) secretion in vivo (20, 23) and in vitro (19-22, 24, 26, 29). The neural loci involved in AVP release contain both ET-1 and ET-3 isoforms, their respective mRNAs, and ET-converting enzyme activity (13,16,28,31). ET A and ET B receptors exist in roughly equal numbers within the hypothalamo-neurohypophysial system. Importantly, ET A receptors are located on magnocellular neurons within the supraoptic and paraventricular nuclei as well as nonvasopressinergic neurons within the hypothalamus (12,30). ET B receptors are distributed in the hypothalamus, most prominently in the organum vasculosum of the lamina terminalis and median eminence (30). Moreover, ET colocalizes with AVP in secretory vesicles of the neural lobe and exerts actions on the posterior pituitary itself (16,21,31). These sites are all integrally involved in the control of AVP secretion.The effects of ET in this system are complex, depending on the isoform...

Opposing Actions of Endothelin-1 on Glutamatergic Transmission onto Vasopressin and Oxytocin Neurons in the Supraoptic Nucleus

“…Although ET-1 has been shown to induce VP secretion from terminals in the neurohypophysis (Ritz et al, 1992;Rossi, 1993Rossi, , 2004Rossi et al, 1997), previous studies using a compartmentalized hypothalamo-neurohypophysial explant have shown that ET A receptor stimulation at a hypothalamic site inhibited VP release (Rossi, 1995(Rossi, , 2004. Accordingly, extracellular recordings of phasically firing MNCs in the SON (characteristic of VP neurons) demonstrated that a majority of neurons were inhibited by ET-1 (Yamamoto et al, 1993).…”

“…The endothelin receptor ET A is localized in the SON (Koseki et al, 1989), while ET B receptors are distributed in the hypothalamus, most prominently in the organum vasculosum of the lamina terminalis and median eminence (Yamamoto and Uemura, 1998). Studies examining the link between endothelin and neuroendocrine output have revealed that ET-1 induces VP secretion both in vitro (Shichiri et al, 1989;Ritz et al, 1992;Chen, 2002, 2006;Rossi, 2004) and in vivo (Rossi et al, 1997a(Rossi et al, ,b, 2008, while intracerebroventricular administration of endothelin stimulates the release of OT (Samson et al, 1991). Furthermore, ET-1 activates both OT and VP MNCs through an action at the subfornical organ (Wall and Ferguson, 1992).…”

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

“…At the hypothalamic level, selective activation of ET A receptors inhibits AVP release from the neurohypophysis. In contrast, stimulation of ET B receptors increases both somatodendritic and neurohypophyseal AVP release (26).…”

“…The actions of ET on the vasopressinergic system are complex and depend on the specific ET isoform, as well as the site of action and the receptor subtype involved (26,41). ET A receptors are located on magnocellular neurons within the supraoptic and paraventricular nucleus and also nonvasopressinergic neurons within the hypothalamus (13,43).…”

Alcohol Tolerance in Large-Conductance, Calcium-Activated Potassium Channels of CNS Terminals Is Intrinsic and Includes Two Components: Decreased Ethanol Potentiation and Decreased Channel Density

“…First, studies of the chronology of tolerance, using the sucrose fade technique, are impeded by the period necessary for the establishment of consistent blood alcohol levels (Knott et al, 2000). Use of the HNS explant allows precise control over dosage and time of exposure to exogenous agents (Rossi, 2004;Somponpun and Sladek, 2004). Second, it is impossible to separate actions of the drug directly on neurons within the HNS from actions of elements originating outside of the HNS, but influencing these neurons.…”