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

ObjectivesThe present study was to assess whether nebivolol could activate β3-adrenergic receptors (ARs) in the human heart.BackgroundNebivolol is a third-generation β-blocker used in the treatment of heart failure. It associates selective β1-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of β3-ARs, but no data are available in the heart.MethodsThe effect of nebivolol (0.1 nmol/l to 10 μmol/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.ResultsNebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 μmol/l: −55 ± 4%, n = 6), which was similar to that obtained with a preferential β3-AR agonist, BRL 37344 (maximum effect obtained at 1 μmol/l: −45 ± 2%, n = 12). The nebivolol effect was not modified by 10 μmol/l nadolol, a β1,2-AR antagonist, but was significantly reduced in the presence of 1 μmol/l L-748,337, a selective β3-AR antagonist, and after pre-treatment with 100 μmol/l NG-monomethyl-L-arginine, an NOS inhibitor.ConclusionsOur study demonstrated that nebivolol activated β3-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.