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.

Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium

“…Assuming that the initial state of receptor activation is similar in samples that come from the same tissue, these plots indicate that the activation state of the b-adrenoceptors has an in¯uence on the functional response to the respective ligands. In a study on the pithed rat, bucindolol but not carvedilol behaved as a partial agonist by producing a dose-related increase in heart rate (Willette et al, 1998). This positive chronotropy of bucindolol was also detected in several other in vivo studies (Deitchman et al, 1980;Marwood et al, 1986), whereas in a study on human myocardium, no increase in adenylate cyclase activity or force of contraction in response to bucindolol or carvedilol could be detected (Hershberger et al, 1990).…”

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

“…12 Another possibility is suggested by our finding that bucindolol has clinically relevant sympathomimetic properties. Bucindolol previously has been proposed to act as a partial agonist in animal models; it exhibited ␤-adrenergic agonist characteristics in anesthetized dogs and rats, 13,16 increased heart rate in pithed rats, 17 and increased cAMP levels in neonatal rat cardiomyocytes. 18 Bucindolol also has agonist-like (guanine nucleotidesensitive) receptor binding properties 14 at the human ␤AR.…”

Characterization of β1‐selectivity, adrenoceptor‐Gs‐protein interaction and inverse agonism of nebivolol in human myocardium

“…Inverse agonism of nebivolol in human myocardium C. Maack et alstudies (Willette et al, 1998;Trochu et al, 1999;Maack et al, 2000) bucindolol had revealed partial agonist eects, yet not in other studies (Hershberger et al, 1990;Bristow et al, 1992), intrinsic activity of b-blockers can be system-dependent.…”

“…A recent study with bucindolol in patients with heart failure (BESTtrial) had to be terminated due to a lack of bene®t (Bristow, 2000). It is currently discussed whether this negative result may be due to comparable high intrinsic activity of bucindolol that has been observed in animal models (Willette et al, 1998) and also human myocardium (Maack et al, 2000). These data indicate that intrinsic activity of b-blockers has to be considered for therapeutic reasons.…”