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.