Vol. 300, Issue 3, 794-801, March 2002

Bucindolol Exerts Agonistic Activity on the Propranolol-Insensitive State of ₁-Adrenoceptors in Human Myocardium

Andreas Bundkirchen, Klara Brixius, Birgit Bölck and Robert H. G. Schwinger

Labor für Herzmuskelphysiologie und Molekulare Kardiologie, Klinik III für Innere Medizin der Universität zu Köln, Köln, Germany

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. 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 ₁-adrenoceptors were performed in isolated muscle preparations after ₁- and ₂-adrenoceptor antagonism (propranolol, 1 µM), inhibition of ₃-mediated inotropic effects (N-nitro-L-arginine, 100 µM) and forskolin treatment (0.3 µM). Positive inotropic response to stimulation of atypical state ₁-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 ₁-adrenoceptors. Thus, the agonistic activity of bucindolol may influence outcome in heart failure patients.