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.
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.
Nearing
B D
BD
Department of Pharmacology, Georgetown University School of Medicine, Georgetown University, Washington, D.C., USA.
Hutter
J J
JJ
Verrier
R L
RL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D012702:Serotonin Antagonists; D014700:Verapamil; C085177:nexopamil; D004110:Diltiazem