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


METHODS
Responses to nebivolol enantiomers were evaluated in rings of thoracic aorta from male Sprague-Dawley rats.


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
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.
Tran Quang
T
T
INSERM, UMR915, l'Institut du Thorax, Nantes, France.
Rozec
B
B
Audigane
L
L
Gauthier
C
C
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism*; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
D001578:Benzopyrans; D004983:Ethanolamines; D011941:Receptors, Adrenergic; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000068577:Nebivolol; D009569:Nitric Oxide