Estradiol coupling to endothelial nitric oxide stimulates gonadotropin-releasing hormone release from rat median eminence via a membrane receptor

The median eminence (ME). which is the common termination field for adenohy pophysiotropic systems, has been shown to produce nitric oxide (NO), a sign aling molecule involved in neuroendocrine secretion. Using an ex vivo techn ique, 17 beta-estradiol exposure to ME fragments, including vascular tissue s, stimulated NO release within seconds in a concentration-dependent manner , whereas 17 alpha-estradiol or testosterone had no effect. 17 beta-Estradi ol conjugated to BSA (E-2-BSA) also stimulated NO release, suggesting media tion by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibi tor, antagonized the action of both 17 beta-estradiol and E-2-BSA. Furtherm ore, estradiol-stimulated NO stimulates GnRH release. This was demonstrated by hemoglobin (a NO scavenger), N-omega-nitro-L-arginine methyl ester, and L-N-5-(1-iminocthyl)ornithine (nitric oxide synthase inhibitors) inhibitio n of estradiol stimulated NO and GnRH release. In this regard, L-N-5-(1-imi noethyl)ornithine, specific for endotheliol constitutive nitric oxide synth ase, was significantly more potent, suggesting that the estradiol-stimulate d NO release arose from vascular endothelial cells. Additionally, the NO-st imulated GnRH release occurs via guanylyl cyclase activation in GnRH nerve terminals, as ODQ, a potent and selective inhibitor of NO-sensitive guanyly l cyclase, abolished the estradiol-stimulated GnRH release. The results sug gest that at physiological concentrations, 17 beta-estradiol may have immed iate actions on ME endothelial cells via nongenomic signaling pathways lead ing to NO-stimulated GnRH release.