Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium

Abstract

1. The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly β1-selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n = 9). 2. The rank order of β1-selectivity as judged by competition experiments to 3H-CGP 12.1777 in the presence of CGP 207.12 A (300 nmol 1-1, Kiβ2) or ICI 118.551 (50 nmol 1-1, Kiβ1) were NEB(Kiβ2/Kiβ1: 40.7) > BIS(15.6) > MET(4.23) > CAR(0.73) > BUC(0.49). 3. The rank order of the negative inotropic potency of the β-adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 μmol 1-1)-stimulated force (IC50) was: MET (0.6 μmol 1-1)>CAR (4.1 μmol 1-1)>NEB (7.0 μmol 1-1). 4. NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 μmol 1-1) pre-treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 μmol 1-1)-stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl-5′-y1 imidodiphosphate (Gpp(NH)p). 5. Although all studied β-adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the β1-selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with β-adrenoceptor antagonists.