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 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.
Bundkirchen
Andreas
A
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann Str. 9, D-50924 Cologne, Germany.
Nguyen
Quang
Q
Brixius
Klara
K
Bölck
Birgit
B
Mehlhorn
Uwe
U
Schwinger
Robert H G
RH
D000262:Adenylyl Cyclases / Q000378:metabolism; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000368:Aged; D001578:Benzopyrans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D004983:Ethanolamines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D000068577:Nebivolol; D011869:Radioligand Assay; D013237:Stereoisomerism; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D000068577:Nebivolol; D005576:Colforsin; D000262:Adenylyl Cyclases; D008790:Metoprolol; D007545:Isoproterenol