Willette R N, Mitchell M P, Ohlstein E H, Lukas M A, Ruffolo R R
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa 19406, USA.
Pharmacology. 1998 Jan;56(1):30-6. doi: 10.1159/000028179.
Many beta-adrenoceptor antagonists are weak partial agonists, possessing significant intrinsic sympathomimetic activity (ISA). Under certain conditions, ISA may be deleterious through stimulation of beta 1- and/or beta 2-adrenoceptors in the heart. Drugs with ISA are particularly problematic in the treatment of congestive heart failure since agents that activate cardiac beta-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 beta-adrenoceptor agonist, isoproterenol, confirming that these drugs are beta-adrenoceptor antagonists. However, cumulative administration of bucindolol (10-1,000 micrograms/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 +/- 6vs. 205 +/- 11 bpm, respectively). In marked contrast, cumulative administration of carvedilol (10-1,000 micrograms/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 micrograms/kg i.v.) was inhibited by treatment with the competitive beta-adrenoceptor antagonist, propranolol (99 +/- 8.7 vs. 26 +/- 2.6 bpm), confirming that the ISA observed with bucindolol was mediated through stimulation of myocardial beta-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 beta-adrenoceptor antagonists in the pithed rat: however, only bucindolol possesses beta-adrenoceptor-mediated ISA.
许多β-肾上腺素受体拮抗剂是弱部分激动剂，具有显著的内在拟交感活性（ISA）。在某些情况下，ISA可能通过刺激心脏中的β1和/或β2肾上腺素受体而产生有害作用。具有ISA的药物在治疗充血性心力衰竭时尤其成问题，因为激活心脏β-肾上腺素受体的药物，如xamoterol，已与心律失常发生率和死亡率的增加相关。卡维地洛最近被批准用于治疗充血性心力衰竭，而布新洛尔目前正针对该适应症进行大型临床试验。在本研究中，在用于研究ISA的标准模型——脊髓麻醉大鼠中评估了布新洛尔和卡维地洛的ISA。两种化合物均对非选择性β-肾上腺素受体激动剂异丙肾上腺素的正性变时作用产生剂量依赖性抑制，证实这些药物是β-肾上腺素受体拮抗剂。然而，在脊髓麻醉大鼠中静脉内累积给予布新洛尔（10 - 1000微克/千克）会导致心率出现显著的剂量相关增加。布新洛尔引起的心率最大增加幅度为异丙肾上腺素所致增加幅度的44%（分别为90±6与205±11次/分钟）。形成鲜明对比的是，在脊髓麻醉大鼠中静脉内累积给予卡维地洛（10 - 1000微克/千克）对静息心率没有显著影响。静脉内给予布新洛尔（1000微克/千克）引起的心率最大增加被竞争性β-肾上腺素受体拮抗剂普萘洛尔抑制（99±8.7与26±2.6次/分钟），证实观察到的布新洛尔的ISA是通过刺激心肌β-肾上腺素受体介导的。没有ISA的卡维地洛拮抗了布新洛尔的ISA，并且在阻断布新洛尔的ISA方面与普萘洛尔同样有效（99±8.7与27±2.3次/分钟）。总之，布新洛尔和卡维地洛在脊髓麻醉大鼠中都是有效的β-肾上腺素受体拮抗剂：然而，只有布新洛尔具有β-肾上腺素受体介导的ISA。
