Published Online
on July 7, 2003

A more recent version of this article appeared on July 22, 2003

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Submitted on February 18, 2003
Revised on April 1, 2003
Accepted on April 4, 2003

349Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human ₁-Adrenergic Receptor

Christoph Maack MD, Michael Böhm MD, Lydia Vlaskin MS, Ewtim Dabew MS, Kristina Lorenz , Hans-Joachim Schäfers MD, PhD, Martin J. Lohse MD, and Stefan Engelhardt MD, PhD^*

From the Klinik und Poliklinik für Innere Medizin III (C.M., M.B., E.D.) and the Klinik für Herz- und Thoraxchirurgie (H.-J.S.), Universität des Saarlandes, Homburg/Saar; and the Institut für Pharmakologie und Toxikologie (L.V., C.L., M.J.L., S.E.), Universität Würzburg, Würzburg, Germany.

^* To whom correspondence should be addressed. E-mail: engelhardt{at}toxi.uni-wuerzburg.de.

Background--In contrast to other -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 -adrenergic receptors (-ARs) in the respective tissues.

Methods and Results--On isolated right atria from transgenic mice with cardiac overexpression of human ₁-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 ₁-AR. In human failing myocardium, its partial agonist activity is masked by increased activation states of -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 ₁-AR.

Key words: receptors, adrenergic, beta • inotropic agents • heart failure • genetics

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