Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human β ₁ -Adrenergic Receptor

BACKGROUND: In contrast to other beta-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 beta-adrenergic receptors (beta-ARs) in the respective tissues. METHODS AND RESULTS: On isolated right atria from transgenic mice with cardiac overexpression of human beta1-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 micromol/L, 90 minutes, subsequent washout), bucindolol significantly increased the force of contraction (P<0.001 vs control). In nonfailing atrial myocardium, isoproterenol pretreatment (1 micromol/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 beta1-AR. In human failing myocardium, its partial agonist activity is masked by increased activation states of beta-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 beta1-AR.