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Neurohypophyseal Hormones: From Genomics and Physiology to Disease

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

¹Departments of Medicine and Physiology, Wayne State University School of Medicine and John D. Dingell VA Medical Center; and ²Department of Physiology, Wayne State University School of Medicine and Henry Ford Hospital System, Detroit, Michigan

Submitted 3 October 2005 ; accepted in final form 7 December 2005

Endothelin (ET) peptides stimulate vasopressin (AVP) secretion via ET_B 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 ET_B 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^–/–) and their wild-type parent strain. Whole explants in standard culture or only the hypothalamus of compartmentalized explants was exposed to the ET_B selective agonist, IRL 1620 (10^–13 to 10^–8 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 ± 63 (rat) and 422 ± 112% basal·explant^–1·h^–1 (mouse). Sodium nitroprusside (SNP; 0.1 mM) suppressed maximal AVP release to basal values. N-nitro-L-arginine methyl ester (L-NAME, 0.1 µM), which did not itself stimulate AVP secretion, more than doubled the response to 1 pM IRL 1620, from 136 ± 28 to 295 ± 49% basal·explant^–1·h^–1 (P < 0.05) by rat explants. Explants from wild-type mice responded similarly. Explants from nNOS^–/– mice had higher basal AVP secretory rate in response to 1 pM IRL 1620: 271 ± 48 compared with 150 ± 24% basal·explant^–1·h^–1 (P < 0.05) from wild-type murine explants. In the nNOS^–/–, SNP suppressed stimulated release, and L-NAME exerted no additional stimulatory effect: 243 ± 38% basal·explant^–1·h^–1. Thus nitric oxide inhibits the AVP secretory response induced by ET_B 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