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

Abstract

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 β ₁ -ARs, bucindolol led to a greater increase in beating frequency ( P P P r =−0.75 and −0.74, respectively; P Conclusions— We conclude that bucindolol is a partial agonist at the human β ₁ -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 β ₁ -AR.