1 Nebivolol, a selective b-adrenoceptor (b 1 -AR) antagonist, induces vasodilatation by an endothelium-and NO-cGMP-dependent pathway. However, the mechanisms involved in the vascular effect of nebivolol have not been established. Thus, we evaluated the role of a 1 and b 3 -ARs in nebivolol-induced vasodilatation. 2 The responses to nebivolol were investigated in vitro in thoracic aortic rings isolated from male Sprague-Dawley rats. 3 Nebivolol (0.1-10 mM) significantly shifted the concentration-response curve to phenylephrine, an a 1 -AR agonist, to the right in a concentration-dependent manner (pA 2 ¼ 6.5). Conversely, the concentration-response curve to endothelin 1 (ET1) was unaffected by nebivolol. 4 In ET1-precontracted rings, nebivolol induced a concentration-dependent relaxation, which was unaffected by nadolol (a b 1 /b 2 -AR antagonist) but was significantly reduced by L-748,337 (a b 3 -AR antagonist), endothelium removal or pretreatment with L-NMMA (an NOS inhibitor). Similar results were obtained with a b 3 -AR agonist, SR 58611A. 5 It was concluded that, in rat aorta, nebivolol-induced relaxation results from both inhibition of a 1 -ARs and activation of b 3 -ARs. In addition, we confirmed that the endothelium and the NO pathway are involved in the vascular effect of nebivolol. The identification of these vascular targets of nebivolol indicate that it has therapeutic potential for the treatment of pathological conditions associated with an elevation of sympathetic tone, such as heart failure and hypertension.

Background and purpose: Nebivolol is a highly selective b1-adrenoceptor antagonist with b3-adrenoceptor agonist properties and is a racemate mixture of D-and L-enantiomers. However, the cellular mechanisms of the effects of each enantiomer are not yet clear and are a matter for debate. The aim of the present experiments was to determine the adrenoceptors involved in the vascular effects of D-and L-enantiomers of nebivolol in rat thoracic aorta. Experimental approach: Responses to nebivolol enantiomers were evaluated in rings of thoracic aorta from male SpragueDawley rats.), but not L-nebivolol, significantly shifted to the right the concentration-response curve to phenylephrine, an a1-adrenoceptor agonist, in a concentration-dependent manner. For the following experiments, aortic rings were constricted with endothelin 1 and now both enantiomers produced an endothelium-dependent relaxation of the rings involving the nitric oxide pathway. This relaxation was not modified by 1 mmol·L -1 CGP 20,712A (b1-adrenoceptor antagonist), but significantly blunted by 7 mmol·L -1 L-74,8337 (b3-adrenoceptor antagonist). However, only the vasorelaxation induced by D-nebivolol was significantly reduced by 1 mmol·L -1 ICI 118,551 (b2-adrenoceptor antagonist). Conclusions and implications:Our results suggest that the nebivolol enantiomers act on different targets. D-nebivolol induced vasorelaxation by activating b2-and b3-adrenoceptors and antagonizing a1-adrenoceptors. L-nebivolol induced vasorelaxation by activating only b3-adrenoceptors in our model. Our results emphasize that nebivolol is a b1-adrenoceptor antagonist with several important pharmacological differences from other b1-adrenoceptor antagonists.