Bucindolol displays intrinsic sympathomimetic activity in human myocardium

Background - Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results - Myocardial strips (≈ 1 mm³) obtained from rat and nonfailing human hearts were confirmed to be viable for ≥48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by ≈25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64±0.25-fold and 2.00±0.27-fold over control, respectively, P<0.01 for human tissue). Conclusions - Bucindolol exhibits ≈60% of the β-adrenergic agonist activity of xamoterol in normal human myocardial tissue.