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). 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 l−1, Kiβ2) or ICI 118.551 (50 nmol l−1, Kiβ1) were NEB(Kiβ2/Kiβ1: 40.7)>BIS(15.6)>MET(4.23)>CAR(0.73)>BUC(0.49). 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 l−1)‐stimulated force (IC50) was: MET (0.6 μmol l−1)>CAR (4.1 μmol l−1)>NEB (7.0 μmol l−1). 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 l−1) pre‐treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 μmol l−1)‐stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl‐5′‐yl imidodiphosphate (Gpp(NH)p). 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. British Journal of Pharmacology (2001) 133, 1330–1338; doi:

1 The present study investigated the eects of the preferential b 3 -AR agonist BRL 37344 (BRL) on force of contraction (FOC), Ca 2+ -transient and eNOS-activity in human right atrial myocardium. 2 BRL concentration-dependently caused an increase in FOC that was paralleled by an increase in Ca 2+ -transient and a shortening of time to half peak relaxation (T0.5T). These eects were abolished in the presence of propranolol (0.3 mM).3 BRL acted as a competitive antagonist towards isoprenaline and in binding experiments it was shown to have a distinct anity towards b 1/2 -AR. 4 In immunohistochemical experiments BRL (10 mM) increased detection of activated eNOS. This eect remained constant in the presence of propranolol (0.3 mM). 5 BRL increased directly detected NO in DAF-staining experiments. This increase was signi®cantly smaller in the presence of the NO-inhibitor L-NAME. 6 The inotropic eects of BRL were not changed in the presence of L-NMA. 7 These results suggest that the inotropic eects of BRL in human atrium are mediated via b 1/2 -AR, whereas the increase of atrial eNOS-activity is due to b 3 -adrenergic stimulation. This increase in eNOS-activity did not in¯uence atrial myocardial contractility. In conclusion, this study shows that b 3 -adrenergic stimulation is present in human atrium, but may not be functionally as signi®cant as in the left ventricle.

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In congestive heart failure patients, treatment with ␤-adrenoceptor antagonists improves symptoms and decreases mortality. However, intrinsic sympathomimetic activity of ␤-adrenoceptor antagonists might be disadvantageous in chronic heart failure. The nonselective ␤ 1 -and ␤ 2 -adrenoceptor antagonist bucindolol has failed to decrease mortality in clinical trials. A putative ␤ 4 -adrenoceptor, which mediates positive inotropic effects by activation of the adenylate cyclase has been described. Recently, this putative ␤ 4 -adrenoceptor has been identified to be a propranolol-insensitive state of the ␤ 1 -adrenoceptor. The present study aimed to characterize whether bucindolol exhibits agonistic activity on this atypical ␤ 1 -adrenoceptor state as one possible reason for clinical inefficiency.

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