Mixedβ3‐adrenoceptor agonist andα1‐adrenoceptor antagonist properties of nebivolol in rat thoracic aorta

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Abstract
Nebivolol, a selectiveβ‐adrenoceptor (β1‐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 ofα1andβ3‐ARs in nebivolol‐induced vasodilatation. The responses to nebivolol were investigatedin vitroin thoracic aortic rings isolated from male Sprague–Dawley rats. Nebivolol (0.1–10 μM) significantly shifted the concentration–response curve to phenylephrine, anα1‐AR agonist, to the right in a concentration‐dependent manner (pA2=6.5). Conversely, the concentration–response curve to endothelin 1 (ET1) was unaffected by nebivolol. In ET1‐precontracted rings, nebivolol induced a concentration‐dependent relaxation, which was unaffected by nadolol (aβ1/β2‐AR antagonist) but was significantly reduced by L‐748,337 (aβ3‐AR antagonist), endothelium removal or pretreatment with L‐NMMA (an NOS inhibitor). Similar results were obtained with aβ3‐AR agonist, SR 58611A. It was concluded that, in rat aorta, nebivolol‐induced relaxation results from both inhibition ofα1‐ARs and activation ofβ3‐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. British Journal of Pharmacology(2006)147, 699–706. doi:10.1038/sj.bjp.0706648

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