Mechanism of Action of Bucindolol in Human Ventricular Myocardium

Abstract

The mechanism of action of the .beta.-receptor antagonist bucindolol was examined in human ventricular myocardium. Bucindolol was found to be a high-affinity competitive .beta.-blocking agent as determined by bucindolol-[125I]-iodocyanopindolol (ICYP) competition curves (KI = 3.7 .+-. 1.3 .times. 10-9 M, n = 9 M, n = 10). This value was in general agreement with bucindolol KB''s, determined by antagonism of isoproterenol-stimulated adenylate cyclase activity (KB = 2.8 .+-. 0.55 .times. 10-9 M, n = 5) or isoproterenol-augmented contraction of right ventricular trabecular (KB = 2.9 .+-. 1.9 .times. 10-9 M, n = 3). In contrast, the .alpha.1-receptor KI, determined at bucindolol-125IBE2252 (IBE) competition binding in rat cardiac membranes, was 1.2 .times. 10-7 M. Bucindolol exhibited no .beta.1- or .beta.2-receptor subtype selectivity as deduced from blockade of the .beta.-agonist-coupled adenylate cyclase system, receptor-binding studies with preparations of human ventricular myocardium with predominantly .beta.1 or .beta.2 receptors, or receptor-binding studies in model systems consisting of .beta.1 (guinea pig myocardial membranes) or .beta.2 receptors (human mononuclear and frog myocardial membranes). In membranes derived from human ventricular myocardium and human lymphocytes, bucindolol recognized a high-affinity agonist-binding site as determined by guanine nucleotide modulation of competition-binding curves. Although bucindolol has measurable intrinsic sympathomimetic activity (ISA) in some animal systems, no increase in adenylate cyclase activity as muscle contraction was detected in preparations of human heart. In conclusion, bucindolol is a high-affinity nonselective .beta.-receptor antagonist with no evidence of intrinsic sympathomimetic activity in human ventricular myocardium.