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

摘要

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 beta1-adrenoceptor selective antagonist metoprolol was used. After pre-stimulation of force of contraction with forskolin (0.3 microM) or isoprenaline (0.01 microM), force developement was decreased only at high concentrations (> or =300 nM) of nebivolol or its enantiomers in isolated trabeculae. Nebivolol and its enantiomers, in contrast to metoprolol (0.4 microM: -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 microM) influenced myofibrillar Ca2+ responsiveness. Nebivolol and the D-enantiomer, but not the L-enantiomer (all 0.5 microM), improved the frequency-dependent force generation. D-Nebivolol, in contrast to L-nebivolol, was a beta1-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.