Different intrinsic activities of bucindolol, carvedilol and metoprolol inhuman failing myocardium

1 Clinical studies have shown different effects of P-blockers on the beta-a drenergic system, tolerability and outcome in patients with heart failure. 2 The study examines beta-adrenoceptor-G-protein coupling and intrinsic act ivity of bucindolol, carvedilol and metoprolol in human ventricular myocard ium. 3 Radioligand binding studies ([I-125]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Function al experiments were carried out in isolated muscle preparations of human le ft ventricular myocardium from failing hearts. 4 Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-a drenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable bi nding. 5 All beta-blockers antagonized isoprenaline-induced enhancement of contrac tility. 6 In preparations in which the coupling of the stimulatory G-protein to ade nylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol incre ased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89.4+/-2.2% (P<0.01 metoprolol vs carvedilol a nd bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7 It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ven tricular myocardium, bucindolol displays substantially higher intrinsic act ivity than metoprolol and carvedilol. Bucindolol can behave as partial agon ist or partial inverse agonist depending on the examined tissue. 8 Differences in intrinsic activity may contribute to differences in beta-a drenoceptor regulation and possibly to differences in tolerability and outc omes of patients with heart failure.