Potent antifibrillatory effect of combined blockade of calcium channels and 5-HT2 receptors with nexopamil during myocardial ischemia and reperfusion in dogs: Comparison to diltiazem
Potent antifibrillatory effect of combined blockade of calcium channels and 5-HT2 receptors with nexopamil during myocardial ischemia and reperfusion in dogs: Comparison to diltiazem
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DOI：
10.1097/00005344-199606000-00003
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发表时间：
1996-01-01
影响因子：
3
通讯作者：
Verrier, RL
中科院分区：
文献类型：
--
作者：
Nearing, BD;Hutter, JJ;Verrier, RL
临床试验表明，钠或钾通道阻滞剂可增加心源性猝死的发生率，而β-阻滞剂仅可部分降低心源性猝死的发生率，这强调了对新型抗心律失常治疗的需求。我们研究了具有钙通道和5-HT 2受体阻滞剂独特组合的奈索帕米在预防犬冠状动脉闭塞和突然再灌注期间的室性心动过速（VT）和室颤（VF）以及降低T波电交替幅度方面的疗效。结果与L-型钙通道阻滞剂单独地尔硫卓进行了比较。在氯醛糖麻醉的狗中，在左前降支（LAD）冠状动脉闭塞和释放的10分钟期间测试nexopamil的作用。T波电交替幅度通过复解调来评估。该药物降低了闭塞期间VT的发生率（从5/6到0/6，p < 0.03）和VT/VF在突然再灌注期间（从5/6到0/6，p < 0.03）并抑制由阻塞引起的T波电交替幅度增加（从14.62 +/- 3.96到1.39 +/- 0.34 mV x ms，p < 0.01）和再灌注（从17.33 +/- 4.67到2.34 +/- 0.77 mV x ms，p < 0.01）。当30秒的左星状神经节刺激（10 V，5 ms脉冲，10 Hz）叠加在闭塞上时，nexopamil降低了VT/VF发生率（从11例中的8例降低到11例中的4例，p < 0.05）和T波电交替幅度（从24.80 +/- 5.05到15.81 +/- 5.09 mV x ms，p < 0.05）。在冠状动脉闭塞期间，单独使用地尔硫卓进行钙通道阻滞可降低室性快速性心律失常的发生率（从5/10降至1/10，p < 0.05）和T波电交替幅度（从16.75 +/- 3.06降至2.87 +/- 1.23 mV x ms，p < 0.05）。在再灌注过程中，地尔硫卓降低心律失常发生率（从5/8降至2/8）没有统计学意义，尽管T波电交替降低（从28.60 +/- 3.43降至8.27 +/- 3.73 mV x ms，p < 0.05）是显著的。因此，nexopamil在预防再灌注诱导的心律失常方面上级于地尔硫卓。Nexopamil在冠状动脉闭塞和突然再灌注期间的显著抗心律失常作用通过T波电交替幅度可靠地追踪。由于保护的主要成分可以通过地尔硫卓阻断L型钙通道来复制，因此nexopamil的抗心律失常作用似乎主要是由于阻断该通道。Nexopamil通过阻断5-HT 2受体的抗血小板作用可能对再灌注心律失常提供额外的保护。
The need for novel antifibrillatory therapy is underscored by clinical trials indicating that the incidence of sudden cardiac death is increased by sodium or potassium channel blockade and is only partially reduced by beta-blockade. We examined the efficacy of nexopamil, which possesses the unique combination of calcium channel and 5-HT2 receptor blockade, in preventing ventricular tachycardia (VT) and fibrillation (VF) and reducing T-wave alternans magnitude during coronary artery occlusion and abrupt reperfusion in dogs. The results were compared with L-type calcium channel blockade alone with diltiazem. The effect of nexopamil was tested during a 10-min period of left anterior descending (LAD) coronary artery occlusion and release in chloralose-anesthetized dogs. T-wave alternans magnitude was assessed by complex demodulation. The drug reduced the incidence of VT during occlusion (from 5 of 6 to 0 of 6, p < 0.03) and VT/VF during abrupt reperfusion (from 5 of 6 to 0 of 6, p < 0.03)and suppressed the T-wave alternans magnitude increase induced by occlusion (from 14.62 +/- 3.96 to 1.39 +/- 0.34 mV x ms, p < 0.01) and reperfusion (from 17.33 +/- 4.67 to 2.34 +/- 0.77 mV x ms, p < 0.01). When 30-s left stellate ganglion stimulation (10 V, 5-ms pulses, 10 Hz) was superimposed on occlusion, nexopamil reduced the VT/VF incidence (from 8 of 11 to 4 of 11, p < 0.05) and T-wave alternans magnitude (from 24.80 +/- 5.05 to 15.81 +/- 5.09 mV x ms, p < 0.05). Calcium channel blockade alone with diltiazem decreased the incidence of ventricular tachyarrhythmias (from 5 of 10 to 1 of 10, p < 0.05) and T-wave alternans magnitude (from 16.75 +/- 3.06 to 2.87 +/- 1.23 mV x ms, p < 0.05) during coronary artery occlusion. During reperfusion, diltiazem's reduction in arrhythmia incidence (from 5 of 8 to 2 of 8) was not statistically significant, although the decrease in T-wave alternans (from 28.60 +/- 3.43 to 8.27 +/- 3.73 mV x ms, p < 0.05) was significant. Therefore, nexopamil was superior to diltiazem in protecting against reperfusion-induced arrhythmias. Nexopamil's significant antifibrillatory effect during both coronary artery occlusion and abrupt reperfusion is reliably tracked by T-wave alternans magnitude. Because the major component of the protection could be reproduced by blockade of the L-type calcium channel with diltiazem, nexopamil's antiarrhythmic action appears to be due mainly to blockade of this channel. Nexopamil's antiplatelet action through blockade of 5-HT2 receptors may confer additional protection against reperfusion arrhythmias.