Involvement of the beta3 adrenoceptor in nebivolol-induced vasorelaxation in the rat aorta.
Nebivolol is a highly selective beta(1) adrenoceptor blocker with additional vasodilating properties. Although it has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) and cGMP dependent, the receptor that mediates these actions remains controversial, and serotonergic as well as beta-adrenergic pathways may be involved. Therefore, functional experiments investigating the receptor involved in nebivolol-induced vasorelaxation were performed in the rat aorta. Isolated aortic rings were exposed to cumulative concentrations of nebivolol. Nebivolol concentrations of 3 micromol/L and higher caused vasorelaxation, which was inhibited by the presence of the NO synthase inhibitor l-NNA (100 micromol/L), or by mechanical removal of the endothelium. Exposure of the vessel rings to the selective 5-HT(1A) antagonist NAN-190 (1 micromol/L) or the 5-HT(1/2) antagonist methysergide (1 micromol/L) did not influence nebivolol-induced vasorelaxation. Similarly, the incubation with the beta(2)-adrenoceptor antagonist butoxamine (50 micromol/L) did not prevent vasorelaxation. The selective beta(3)-adrenoceptor antagonist S-(-)-cyanopindolol (1 micromol/L), however, significantly counteracted the nebivolol-induced vasorelaxation. Furthermore, exposure of the aortic rings to cumulative concentrations of the beta(3) selective adrenoceptor agonist BRL37344 caused, like nebivolol, NO-dependent vasorelaxation that was antagonized by S-(-)-cyanopindolol. The results suggest that nebivolol-induced NO-dependent vasorelaxation is, at least in part, caused by a beta(3)-adrenoceptor agonistic effect.
de Groot
Annemieke A
AA
Department of Pharmacology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. a.a.degroot@amc.uva.nl
Mathy
Marie-Jeanne
MJ
van Zwieten
Pieter A
PA
Peters
Stephan L M
SL
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D004347:Drug Interactions; D004983:Ethanolamines / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D000068577:Nebivolol; D051381:Rats; D011921:Rats, Inbred WKY; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000068577:Nebivolol