Lack of inverse agonistic activity of nebivolol, its d- and l-enantiomers and of in vivo metabolized nebivolol in human myocardium

Abstract

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 β 1-adrenoceptor selective antagonist metoprolol was used. After pre-stimulation of force of contraction with forskolin (0.3 μM) or isoprenaline (0.01 μM), force developement was decreased only at high concentrations (≥300 nM) of nebivolol or its enantiomers in isolated trabeculae. Nebivolol and its enantiomers, in contrast to metoprolol (0.4 μM: −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 nebivolol in pharmacological concentrations. Neither d- nor l-nebivolol (30 μM) influenced myofibrillar Ca 2+ responsiveness. Nebivolol and the d-enantiomer, but not the l-enantiomer (all 0.5 μM), improved the frequency-dependent force generation. d-Nebivolol, in contrast to l-nebivolol, was a β 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.