Lack of inverse agonistic activity of nebivolol, Its D- and L-enantiomers and of in vivo metabolized nebivolol in human myocardium

The pharmacological profile of nebivolol may be mediated by its enantiomers and/or its hydroxylated metabolites. Therefore, the cardiac effects of the nebivolol enantiomers as well as of serum specimens containing hydroxylated nebivolol metabolites were studied in human myocardium. For control, the beta(1)-adrenoceptor selective antagonist metoprolol was used. After pre-stimulation of force of contraction with forskolin (0.3 muM) or isoprenaline (0.01 muM), force developement was decreased only at high concentrations (greater than or equal to300 nM) of nebivolol or its enantiomers in isolated trabeculae. Nebivolol and its enantiomers, in contrast to metoprolol (0.4 muM: -72% basal force), produced only minor negative intropic effects in isolated trabeculae under basal conditions. Basal force of contraction was not decreased by in vivo metabolized nebivolot in pharmacological concentrations. Neither D- nor L-nebivolol (30 muM) influenced myofibrillar Ca2+ responsiveness. Nebivolol and the D-enantiomer, but not the L-enantiomer (all 0.5 muM), improved the frequency-dependent force generation. D-Nebivolol, in contrast to L-nebivolol, was a beta(1)-adrenoceptor selective compound in membrane preparations from non-failing donor hearts. In conclusion, nebivolol and its enantiomers as well as in vivo metabolized nebivolol produce only minor negative inotropic effects. This and the finding that nebivolol and its D-enantiomer improve the frequency-dependent force generation may be of particular advantage when treating patients with already compromised cardiac function. (C) 2003 Elsevier B.V. All rights reserved.