title: Nebivolol: a selective beta(1)-adrenergic receptor antagonist that relaxes vascular smooth muscle by nitric oxide- and cyclic GMP-dependent mechanisms.
abstract: Nebivolol is a highly selective beta(1)-adrenergic receptor antagonist that also possesses vasodilator properties that are attributed largely to nitric oxide (NO). The objective of the present study was to elucidate in more detail the mechanisms by which nebivolol relaxes vascular smooth muscle. In the canine species, nebivolol caused relaxation of isolated precontracted rings of coronary artery and pulmonary artery largely by endothelium-dependent, NO-dependent, and cyclic GMP-dependent mechanisms. Vasorelaxation was inhibited by N(G)-methylarginine, and this inhibition was reversed by addition of excess L-arginine. Moreover, the vasorelaxant responses to nebivolol were markedly inhibited by oxyhemoglobin, methylene blue, and 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), whereas vasorelaxation was enhanced by zaprinast. Rat aortic ring preparations, however, relaxed in response to nebivolol by both endothelium-dependent and endothelium-independent mechanisms, both involving NO, and cyclic GMP. Endothelium-dependent and endothelium-independent vasorelaxation were inhibited by oxyhemoglobin, methylene blue, and ODQ. However, only endothelium-dependent vasorelaxation in response to nebivolol was inhibited by N(G)-methylarginine. Additional experiments ruled out other endothelium-independent vasorelaxant mechanisms. In conclusion, the vasodilator responses to nebivolol involve NO and cyclic GMP in both vascular endothelial and smooth muscle cells.
authors.affiliation: Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90095-1735, USA. lignarro@mednet.ucla.edu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Russell E
authors.initials: RE
authors.lastname: Byrns
authors.forename: Kim
authors.initials: K
authors.lastname: Trinh
authors.forename: Manisha
authors.initials: M
authors.lastname: Sisodia
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Buga
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D018342:Receptors, Adrenergic, beta-1; D000068577:Nebivolol; D009569:Nitric Oxide; D006152:Cyclic GMP