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

1 The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly beta (1)-selective adrenoc eptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisopro lol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). 2 The rank order of beta (1)-selectivity as judged by competition experimen ts to H-3-CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l(-1), K(i) beta (2)) or ICI 118.551 (50 nmol l(-1), K(i)beta (1)) were NEB(K(i)beta (2 )/K(i)beta (1): 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 beta -adrenocepto r antagonists measured in left ventricular trabeculae (dilated cardiomyopat hy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (l mu mol l(-1))-stimulated force (IC50) was: MET (0.6 mu mol l(-1)) > CAR (4.1 mu mol l(-1)) > NEB (7.0 mu mol l(-1)). 4 NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic acti vity (ISA) as determined by measurements of force development in forskolin (0.3 mu mol l(-1)) pre-treated left ventricular trabeculae, nor by measurin g adenylate cyclase activity in forskolin (0.3 mu mol l(-1))stimulated assa ys (crude membranes). This also holds true for radioligand binding assays w ith or without guanine nucleotide guanyl-5'-yl imidodiphosphate (Gpp(NH)p). 5 Although all studied beta -adrenoceptor antagonists lack intrinsic sympat homimetic activity (ISA), they differ in the beta (1)-selectivity as well a s in their direct negative inotropic action. These differences as well as t he mode of extracardiac action may have an impact on outcome of patients tr eated with beta -adrenoceptor antagonists.