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 beta(1)-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 beta(1)-selectivity as judged by competition experiments to (3)H-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-adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 micromol l(-1))-stimulated force (IC(50)) was: MET (0.6 micromol l(-1)) > CAR (4.1 micromol l(-1)) > NEB (7.0 micromol l(-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 micromol l(-1)) pre-treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 micromol 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). 5. Although all studied beta-adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the beta(1)-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 beta-adrenoceptor antagonists.

Figure 1

Chemical structures of the different β-adrenoceptor antagonists.

Figure 2

β-adrenoceptor selectivity. Experiments with nebivolol (A), bisoprolol (B), metoprolol (C), bucindolol (D) and carvedilol (E) were performed in the presence of 0.3 μmol l⁻¹ CGP 207.12A or 0.05 μmol l⁻¹ ICI 118.551 in order to obtain competition at a homogeneous population of β₂- or β₁-adrenoceptors on left ventricular myocardial membranes obtained from human myocardium.

Figure 3

Rank order of β₁-adrenoceptor selectivity of nebivolol, bisoprolol, metoprolol, bucindolol and carvedilol.

Figure 4

Original tracings illustrating the effect of a low (0.3 μmol l⁻¹) and high (10 μmol l⁻¹) concentration of metoprolol, carvedilol and nebivolol in isoprenaline (1 μmol l⁻¹) pre-stimulated isolated, electrically driven (1 Hz) trabeculae of human failing myocardium.

Figure 5

Percentage changes of isoprenaline pre-stimulated force of contraction obtained in human left ventricular failing myocardium after application of metoprolol, carvedilol and nebivolol.

Figure 6

Concentration-response curves for the cardiac effects of the β-adrenoceptor antagonists metoprolol, carvedilol and nebivolol in human left ventricular non-failing myocardium after pre-stimulation with forskolin.

Figure 7

Influence of bucindolol and nebivolol on adenylate cyclase activity in crude membrane preparations of human left ventricular non-failing myocardium.

Figure 8

Effect of Gpp(NH)p on ³H-CGP 12.177 binding experiments in the presence of isoprenaline, nebivolol, carvedilol and bucindolol in human non-failing left ventricular myocardium.