Investigation of the different adrenoceptor targets of nebivolol enantiomers in rat thoracic aorta.

Background and Purpose: Nebivolol is a highly selective beta(1)-adrenoceptor antagonist with beta(3)-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 Sprague-Dawley rats.
Key Results: D-nebivolol (0.1-10 micromol.L(-1)), but not L-nebivolol, significantly shifted to the right the concentration-response curve to phenylephrine, an alpha(1)-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 micromol.L(-1) CGP 20,712A (beta(1)-adrenoceptor antagonist), but significantly blunted by 7 micromol.L(-1) L-74,8337 (beta(3)-adrenoceptor antagonist). However, only the vasorelaxation induced by D-nebivolol was significantly reduced by 1 micromol.L(-1) ICI 118,551 (beta(2)-adrenoceptor antagonist).
Conclusions and Implications: Our results suggest that the nebivolol enantiomers act on different targets. D-nebivolol induced vasorelaxation by activating beta(2)- and beta(3)-adrenoceptors and antagonizing alpha(1)-adrenoceptors. L-nebivolol induced vasorelaxation by activating only beta(3)-adrenoceptors in our model. Our results emphasize that nebivolol is a beta(1)-adrenoceptor antagonist with several important pharmacological differences from other beta(1)-adrenoceptor antagonists.