title: Estrogen receptor-mediated vascular responsiveness to nebivolol: a novel endothelium-related mechanism of therapeutic vasorelaxation.
abstract: Nebivolol is a highly selective and lipophilic beta1-adrenergic receptor antagonist with vasodilating characteristics attributed mainly to endothelial generation of nitric oxide (NO). Coincidently, rapid vascular vasodilating effects of estradiol are also widely reported and membrane-initiated signaling by estrogen receptor (ER), leading to generation of NO, parallels the vasodilating effects observed for nebivolol. Thus, we hypothesized that the NO-dependent vasodilating effect attributed to nebivolol may be partially mediated through its interaction with the membrane-associated form of ER. The objective of this study was to examine the ER-mediated/endothelium-dependent vascular responses to nebivolol and the specific binding properties of nebivolol to ER. In isolated rat aortic rings, the endothelium-dependent vasodilating effect of nebivolol was significantly blocked by the use of the potent ER antagonist, ICI 182,780. In contrast, in the absence of intact endothelium, nebivolol-induced vasorelaxation was not blocked by ICI 182,780, strongly suggesting that nebivolol-elicited vasorelaxation is partially dependent on ER-mediated pathways. Further, we examined the binding of nebivolol to ER (MCF-7 cells) by radioligand binding assay and revealed specific binding kinetics with an estimated DC50 of 5 x 10 M, coinciding with the approximate EC50 of nebivolol as a vasorelaxant. In conclusion, the endothelium-dependent vascular response to nebivolol is attributed partially to its interaction with ER.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 90095-1735, USA.
authors.forename: Hermes J
authors.initials: HJ
authors.lastname: Garbán
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Buga
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology*; D001667:Binding, Competitive; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004983:Ethanolamines / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D000068577:Nebivolol; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D004965:Estrogen Antagonists; D047629:Estrogen Receptor beta; D004983:Ethanolamines; D014665:Vasodilator Agents; D000068577:Nebivolol; D000077267:Fulvestrant; D004958:Estradiol