Partial agonist activity of bucindolol is dependent on the activation state of the human β₁-adrenergic receptor

Background - In contrast to other β-blockers, bucindolol has failed to reduce mortality in patients with chronic heart failure. It is currently debated whether this is due to partial agonist activity of this agent. We investigated whether conflicting results previously reported concerning the intrinsic activity of bucindolol can be explained by species differences or by different activation states of β-adrenergic receptors (β-ARs) in the respective tissues. Methods and Results - On isolated right atria from transgenic mice with cardiac overexpression of human β₁-ARs, bucindolol led to a greater increase in beating frequency (P<0.05) compared with wild-type mice. The increase amounted to 47% of the effect of xamoterol and was blocked by propranolol. On isolated, electrically stimulated, left ventricular muscle-strip preparations from failing human myocardium, bucindolol did not change the force of contraction under control conditions. In myocardial preparations pretreated with metoprolol (30 μmol/L, 90 minutes, subsequent washout), bucindolol significantly increased the force of contraction (P<0.001 vs control). In nonfailing atrial myocardium, isoproterenol pretreatment (1 μmol/L, 60 minutes) abolished the positive inotropic effect of xamoterol that was present under control conditions (P<0.05 vs control). The inotropic effects of bucindolol or xamoterol were inversely correlated to the inotropic response to forskolin in the respective specimens (r = -0.75 and -0.74, respectively; P<0.005). Conclusions - We conclude that bucindolol is a partial agonist at the human β₁-AR. In human failing myocardium, its partial agonist activity is masked by increased activation states of β-ARs and is unmasked after in vitro pretreatment with metoprolol. Thus, the partial agonist activity of bucindolol is dependent on the activation state of the human β₁-AR.