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

American Journal of Physiology-Regulatory, Integrative and Comp

Beierwaltes²

2006

Self Cite

peptides stimulate vasopressin (AVP) secretion via ETB receptors at hypothalamic loci. Nitric oxide modulates the actions of ET in the cardiovascular system and also influences neurotransmission and specifically suppresses firing of magnocellular neurons. The purpose of these studies was to ascertain whether nitric oxide, generated in response to ETB receptor stimulation, buffers the stimulatory effect of ET and suppresses AVP release. Studies were performed using a pharmacological approach in hypothalamo-neurohypophyseal explants from rats, and an alternative strategy using explants from mice with an inactivating mutation of neuronal NOS (nNOS Ϫ/Ϫ ) and their wild-type parent strain. Whole explants in standard culture or only the hypothalamus of compartmentalized explants was exposed to the ETB selective agonist, IRL 1620 (10 Ϫ13 to 10 Ϫ8 M). Rat and wild-type mouse explants displayed similar responses, although absolute basal release rates were higher from murine explants. Maximal AVP release at 0.1 nM IRL 1620 was 311 Ϯ 63 (rat) and 422 Ϯ 112% basal⅐explant Ϫ1 ⅐h Ϫ1 (mouse). Sodium nitroprusside (SNP; 0.1 mM) suppressed maximal AVP release to basal values. N -nitro-L-arginine methyl ester (L-NAME, 0.1 M), which did not itself stimulate AVP secretion, more than doubled the response to 1 pM IRL 1620, from 136 Ϯ 28 to 295 Ϯ 49% basal⅐explant Ϫ1 ⅐h Ϫ1 (P Ͻ 0.05) by rat explants. Explants from wild-type mice responded similarly. Explants from nNOS Ϫ/Ϫ mice had higher basal AVP secretory rate in response to 1 pM IRL 1620: 271 Ϯ 48 compared with 150 Ϯ 24% basal⅐explant Ϫ1 ⅐h Ϫ1 (P Ͻ 0.05) from wild-type murine explants. In the nNOS Ϫ/Ϫ , SNP suppressed stimulated release, and L-NAME exerted no additional stimulatory effect: 243 Ϯ 38% basal⅐explant Ϫ1 ⅐h Ϫ1. Thus nitric oxide inhibits the AVP secretory response induced by ETB receptor activation within the hypothalamo-neurohypophyseal system and is generated primarily by the nNOS isoform. The modulation of AVP secretion by ET and also nitric oxide can take place independently from their effects on cerebral blood flow, systemic hemodynamics, or the arterial baroreflex.endothelin; nitric oxide synthase; neuronal nitric oxide synthase; posterior pituitary THE ENDOTHELINS (ET) ARE PEPTIDES that exhibit potent vasoactive actions. ET peptides also participate in neurotransmission and neuromodulation within the central nervous system (12, 16). All components of the ET system, including both ET-1 and ET-3 isoforms, their respective mRNAs, ET-converting enzyme activity and both ET A and ET B receptor subtypes, exist within nonvascular brain tissues, and specifically in loci involved in vasopressin (AVP) secretion (13,15,17,38,45). Moreover, several studies have implicated ET peptides in the regulation of AVP secretion in vivo (24,27,29,30) and in vitro (23-26, 28, 31, 34).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 mag...

Section: Discussionmentioning

confidence: 50%

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

American Journal of Physiology-Regulatory, Integrative and Comp

Beierwaltes²

2006

Self Cite

“…In vitro studies in hypothalamo-neurohypophysial explants indicate that ET B -induced AVP release is stimulated by the N -methyl- d -aspartate (NMDA) receptor and attenuated by γ-aminobutyric acid (GABA) receptor mechanisms (639). The NMDA receptor subtype involved is not known.…”

Section: Endothelin and Humoral Systemsmentioning

confidence: 99%

Regulation of Blood Pressure and Salt Homeostasis by Endothelin

Kohan

Inscho

et al. 2011

Physiological Reviews

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367

459

Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

“…Previous studies from our laboratory (22) implicate an N-methyl-D-aspartate receptor, but other receptors may be involved as well. Although the present data do not directly address the locus of these ET-responsive neurons or whether the projection is monosynaptic or polysynaptic, the Av3V region, which contains neurons excited by ET peptides (29) and includes the organum vasculosum of the lamina terminalis richly endowed with ET B receptors (30), is a candidate locus (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…AVP content of the medium was measured by radioimmunoassay with methods previously reported from our laboratory (20)(21)(22)(23)(24). Samples of medium were diluted 1:50 and directly assayed in duplicate.…”

Section: Methodsmentioning

confidence: 99%

“…After dissection, compartmentalized explants were immediately placed into custom-fabricated sterile incubation chambers that have a two-piece barrier separating the hypothalamus from the posterior pituitary (7,21,22). The explants were positioned onto Teflon mesh with the intact infundibular stalk lying in a 0.33-mm-wide by 0.2-mm-deep notch in the lower half of the barrier.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

American Journal of Physiology-Endocrinology and Metabolism

2004

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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...