Abstract

In congestive heart failure patients, treatment with β-adrenoceptor antagonists improves symptoms and decreases mortality. However, intrinsic sympathomimetic activity of β-adrenoceptor antagonists might be disadvantageous in chronic heart failure. The nonselective β₁- and β₂-adrenoceptor antagonist bucindolol has failed to decrease mortality in clinical trials. A putative β₄-adrenoceptor, which mediates positive inotropic effects by activation of the adenylate cyclase has been described. Recently, this putative β₄-adrenoceptor has been identified to be a propranolol-insensitive state of the β₁-adrenoceptor. The present study aimed to characterize whether bucindolol exhibits agonistic activity on this atypical β₁-adrenoceptor state as one possible reason for clinical inefficiency. For comparison (S)-4-(3′-t-butylamino-1′-hydroxypropoxy)-benzimidozole-2 (CGP 12177), metoprolol, and nebivolol were investigated. Bucindolol did not reveal intrinsic sympathomimetic activity in electrically driven (1 Hz, 37°C), forskolin-stimulated, left ventricular papillary muscle strips (donor hearts, nonfailing; n = 5) and in right auricular trabeculae (bypass operation; n= 4). Functional studies on the propranolol-insensitive state of β₁-adrenoceptors were performed in isolated muscle preparations after β₁- and β₂-adrenoceptor antagonism (propranolol, 1 μM), inhibition of β₃-mediated inotropic effects ( n- nitro-l-arginine, 100 μM) and forskolin treatment (0.3 μM). Positive inotropic response to stimulation of atypical state β₁-adrenoceptors could be demonstrated in right auricular as well as left ventricular human myocardium (CGP 12177 treatment, 10 μM). Under these conditions, also bucindolol, but not metoprolol and nebivolol, significantly increased contractility (all 10 μM). In conclusion, bucindolol but not metoprolol or nebivolol mediate positive inotropic effects in human myocardium due to activation of atypical state β₁-adrenoceptors. Thus, the agonistic activity of bucindolol may influence outcome in heart failure patients.