NO-dependent vasodilation induced by nebivolol in coronary circulation is not mediated by beta-adrenoceptors or by 5 HT 1A-receptors

Nebivolol is a unique ß1-adrenoceptor antagonist which possesses peripheral vasodilator properties dependent on endothelial NO. Nebivolol-induced release of NO was attributed to its L stereoisomer and to its ability to stimulate endothelial ß2, ß3 adrenoceptors or 5-HT1A receptors. Here, in the isolated guinea pig heart we analysed coronary vasodilator potency of L- and D-nebivolol and a possible role of ß2, ß3 adrenoceptors and 5-HT1A receptors in nebivolol-induced vasodilation. Surprisingly, we found that not only L-nebivolol (3-30x10-6 M) but also D-nebivolol (3-30x10-6 M) induced coronary vasodilation, and both responses were inhibited by L-NAME (10-4 M). In contrast with the stereoisomers of nebivolol, atenolol at the equimolar concentrations did induce slight vasoconstriction. The nonselective ß1/ß2- adrenoceptor antagonist - nadolol (10-5 M), the selective ß3-adrenoceptor antagonist - L 748337 (10-6 M) and the 5 HT1A receptor antagonist - NAN 190 (5 x 10-6 M), none of them inhibited coronary vasodilation induced by D- and L-nebivolol. In summary, in the isolated guinea pig heart both D- and L-nebivolol act as coronary vasodilators. Coronary vasodilation induced by stereoisomers of nebivolol is mediated by endothelium-derived NO and does not depend on ß2, ß3 adrenoceptors or 5 HT1A receptors.