Protection Against Programmed Electrical Stimulation-Induced Ventricular Tachycardia and Sudden Cardiac Death by NE-10064, a Class III Antiarrhythmic Drug

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Abstract

Summary:

The electrophysiologic and antifibrillatory properties of NE-10064 were studied in vivo in a conscious canine model of sudden cardiac death. Purpose bred male mongrel dogs weighing 14.5-21.5 kg were anesthetized, and surgical anterior myocardial infarction (MI) was induced by a 2-h occlusion, with reperfusion, of the left anterior descending coronary artery (LAD). Three to 5 days after induction of anterior wall MI, animals were subjected to testing by programmed electrical stimulation (PES). As compared with predrug incidence (12 of 12), NE-10064 (10 mg/kg intravenously, i.v.) reduced (p<0.05) the incidence (8 of 12) of PES-induced ventricular tachycardia (VT). All but 1 control animal remained inducible after vehicle (5% dextrose in water). The cycle length of induced VT was not prolonged by NE-10064 (0.245 ± 0.046 s predrug vs. 0.301 ± 0.060 s postdrug). NE-10064 increased ventricular effective refractory period (VERP 166 ± 5 ms predrug vs. 194 ± 13 ms postdrug, p=0.013), prolonged QTc interval (310 ± 12 ms predrug vs. 350 ± 16 ms postdrug, p=0.004) and prolonged the effective refractory period (ERP) of noninfarcted myocardium (p=0.045). The drug did not affect ECG-indexes of conduction velocity: QRS and P-R intervals were not affected, nor were activation delay and conduction time of noninfarcted and infarcted myocardium. In the sudden cardiac death protocol, NE-10064 protected (p=0.018) against ischemia-induced ventricular fibrillation (VF, 75% survival with drug vs. 25% survival without drug). NE-10064 afforded protection (p=0.040) throughout 14 h posterolateral ischemia in the presence of the previous anterior infarct. The data show that the antiarrhythmic activity of NE-10064 was associated with a significant antifibrillatory effect that may be related to its class III electrophysiologic actions

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