Evaluation of Intrinsic Sympathomimetic Activity of Bucindolol and Carvedilol in Rat Heart

Abstract

Many β-adrenoceptor antagonists are weak partial agonists, possessing significant intrinsic sympathomimetic activity (ISA). Under certain conditions, ISA may be deleterious through stimulation of β₁- and/or β₂-adrenoceptors in the heart. Drugs with ISA are particularly problematic in the treatment of congestive heart failure since agents that activate cardiac β-adrenoceptors, such as xamoterol, have been associated with increases in the incidence of arrhythmia and mortality. Carvedilol was recently approved for the treatment of congestive heart failure, and bucindolol is currently in large clinical trials for this indication. In the present study, the ISA of bucindolol and carvedilol was evaluated in a standard model used to investigate ISA, the pithed rat. Both compounds produced dose-dependent inhibition of the positive-chronotropic effects of the non-selective β-adrenoceptor agonist, isoproterenol, confirming that these drugs are β-adrenoceptor antagonists. However, cumulative administration of bucindolol (10–1,000 µg/kg i.v.) in the pithed rat produced a significant dose-related increase in heart rate. The maximal increase in heart rate produced by bucindolol was 44% of that obtained with isoproterenol (90 ± 6 vs. 205 ± 11 bpm, respectively). In marked contrast, cumulative administration of carvedilol (10–1,000 µg/kg i.v.) had no significant effect on resting heart rate in the pithed rat. The maximal increase in heart rate elicited by bucindolol (1,000 µg/kg i.v.) was inhibited by treatment with the competitive β-adrenoceptor antagonist, propranolol (99 ± 8.7 vs. 26 ± 2.6 bpm), confirming that the ISA observed with bucindolol was mediated through stimulation of myocardial β-adrenoceptors. Carvedilol, which had no ISA, antagonized the ISA of bucindolol, and was as effective as propranolol in blocking the ISA of bucindolol (99 ± 8.7 vs. 27 ± 2.3 bpm). In summary, bucindolol and carvedilol are both potent β-adrenoceptor antagonists in the pithed rat; however, only bucindolol possesses β-adrenoceptor-mediated ISA.