In congestive heart failure patients, treatment with beta-adrenoceptor antagonists improves symptoms and decreases mortality. However, intrinsic sympathomimetic activity of beta-adrenoceptor antagonists might be disadvantageous in chronic heart failure. The nonselective beta1- and beta2-adrenoceptor antagonist bucindolol has failed to decrease mortality in clinical trials. A putative beta4-adrenoceptor, which mediates positive inotropic effects by activation of the adenylate cyclase has been described. Recently, this putative beta4-adrenoceptor has been identified to be a propranolol-insensitive state of the beta1-adrenoceptor. The present study aimed to characterize whether bucindolol exhibits agonistic activity on this atypical beta1-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 degrees 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 beta1-adrenoceptors were performed in isolated muscle preparations after beta1- and beta2-adrenoceptor antagonism (propranolol, 1 microM), inhibition of beta3-mediated inotropic effects (N-nitro-L-arginine, 100 microM) and forskolin treatment (0.3 microM). Positive inotropic response to stimulation of atypical state beta1-adrenoceptors could be demonstrated in right auricular as well as left ventricular human myocardium (CGP 12177 treatment, 10 microM). Under these conditions, also bucindolol, but not metoprolol and nebivolol, significantly increased contractility (all 10 microM). In conclusion, bucindolol but not metoprolol or nebivolol mediate positive inotropic effects in human myocardium due to activation of atypical state beta1-adrenoceptors. Thus, the agonistic activity of bucindolol may influence outcome in heart failure patients.