EVALUATION OF INTRINSIC SYMPATHOMIMETIC ACTIVITY OF BUCINDOLOL AND CARVEDILOL IN RAT-HEART

Many beta-adrenoceptor antagonists are weak partial agonists, possessi ng significant intrinsic sympathomimetic activity (ISA). Under certain conditions, ISA may be deleterious through stimulation of beta(1)- an d/or beta(2)-adrenoceptors in the heart. Drugs with ISA are particular ly problematic in the treatment of congestive heart failure since agen ts that activate cardiac beta-adrenoceptors, such as xamoterol, have b een associated with increases in the incidence of arrhythmia and morta lity. Carvedilol was recently approved for the treatment of congestive heart failure, and bucindolol is currently in large clinical trials f or this indication. In the present study, the ISA of bucindolol and ca rvedilol was evaluated in a standard model used to investigate ISA, th e pithed rat. Both compounds produced dose-dependent inhibition of the positive-chronotropic effects of the non-selective beta-adrenoceptor agonist, isoproterenol, confirming that these drugs are beta-adrenocep tor antagonists. However, cumulative administration of bucindolol (10- 1,000 mu g/kg i.v.) in the pithed rat produced a significant dose-rela ted increase in heart rate. The maximal increase in heart rate produce d by bucindolol was 44% of that obtained with isoproterenol (90 +/- 6 vs. 205 +/- 11 bpm, respectively). In marked contrast, cumulative admi nistration of carvedilol (10-1,000 mu g/kg i.v.) had no significant ef fect on resting heart rate in the pithed rat. The maximal increase in heart rate elicited by bucindolol (1,000 mu g/kg i.v.) was inhibited b y treatment with the competitive beta-adrenoceptor antagonist, propran olol (99 +/- 8.7 vs. 26 +/- 2.6 bpm), confirming that the ISA observed with bucindolol was mediated through stimulation of myocardial beta-a drenoceptors. Carvedilol, which had no ISA, antagonized the ISA of buc indolol, and was as effective as propranolol in blocking the ISA of bu cindolol (99 +/- 8.7 vs. 27 +/- 2.3 bpm). In summary, bucindolol and c arvedilol are both potent beta-adrenoceptor antagonists in the pithed rat; however, only bucindolol possesses beta-adrenoceptor-mediated ISA .