Nebivolol, a Vasodilating Selective β1-Blocker, Is a β3-Adrenoceptor Agonist in the Nonfailing Transplanted Human Heart

Objectives The present study was to assess whether nebivolol could activate beta(3)-adrenergic receptors (ARs) in the human heart. Background Nebivolol is a third-generation beta-blocker used in the treatment of heart failure. It associates selective beta(1)-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of beta(3)-ARs, but no data are available in the heart. Methods The effect of nebivolol (0.1 nmol/l to 10 mu mol/l) upon the developed peak tension was tested in endomyocardial biopsies from human nonrejecting transplanted hearts. Tension was recorded at steady state using a mechanoelectric force transducer. Results Nebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 mu mol/l: -55 +/- 4%, n = 6), which was similar to that obtained with a preferential beta(3)-AR agonist, BRL 37344 (maximum effect obtained at 1 mu mol/l: -45 +/- 2%, n = 12). The nebivolol effect was not modified by 10 mu mol/l nadolol, a beta(1,2)-AR antagonist, but was significantly reduced in the presence of 1 mu mol/l L-748,337, a selective beta(3)-AR antagonist, and after pre-treatment with 100 mu mol/l N-G-monomethyl-L-arginine, an NOS inhibitor. Conclusions Our study demonstrated that nebivolol activated beta(3)-AR in the human ventricle. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as previously described in clinical trials. (J Am Coll Cardiol 2009;53:1532-8) (C) 2009 by the American College of Cardiology Foundation