Published online before print July 7, 2003, doi: 10.1161/01.CIR.0000080325.94345.8B
(Circulation. 2003;108:348.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human ß1-Adrenergic Receptor
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.
Correspondence to Stefan Engelhardt, Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany. E-mail engelhardt{at}toxi.uni-wuerzburg.de
Background— In contrast to other ß-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 ß-adrenergic receptors (ß-ARs) in the respective tissues.
Methods and Results— On isolated right atria from transgenic mice with cardiac overexpression of human ß1-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 ß1-AR. In human failing myocardium, its partial agonist activity is masked by increased activation states of ß-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 ß1-AR.
Key Words: receptors, adrenergic, beta • inotropic agents • heart failure • genetics
This article has been cited by other articles:
 |
|
 |
|
  E. H. Aburawi, A. Berg, P. Liuba, and E. Pesonen Effects of cardiopulmonary bypass surgery on coronary flow in children assessed with transthoracic Doppler echocardiography Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1138 - H1143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Liggett, J. Mialet-Perez, S. Thaneemit-Chen, S. A. Weber, S. M. Greene, D. Hodne, B. Nelson, J. Morrison, M. J. Domanski, L. E. Wagoner, et al. A polymorphism within a conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure PNAS, July 25, 2006; 103(30): 11288 - 11293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Floreani, G. Froldi, L. Quintieri, K. Varani, P. A. Borea, M. T. Dorigo, and P. Dorigo In Vitro Evidence That Carteolol Is a Nonconventional Partial Agonist of Guinea Pig Cardiac {beta}1-Adrenoceptors: A Comparison with Xamoterol J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1386 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|