Involvement of the β3 Adrenoceptor in Nebivolol-Induced Vasorelaxation in the Rat Aorta

Abstract

Nebivolol is a highly selective β1 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 β-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 μmol/L and higher caused vasorelaxation, which was inhibited by the presence of the NO synthase inhibitor l-NNA (100 μmol/L), or by mechanical removal of the endothelium. Exposure of the vessel rings to the selective 5-HT1A antagonist NAN-190 (1 μmol/L) or the 5-HT1/2 antagonist methysergide (1 μmol/L) did not influence nebivolol-induced vasorelaxation. Similarly, the incubation with the β2-adrenoceptor antagonist butoxamine (50 μmol/L) did not prevent vasorelaxation. The selective β3-adrenoceptor antagonist S-(−)-cyanopindolol (1 μmol/L), however, significantly counteracted the nebivolol-induced vasorelaxation. Furthermore, exposure of the aortic rings to cumulative concentrations of the β3 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 β3-adrenoceptor agonistic effect.