ANTIFIBRILLATORY EFFICACY OF LONG-TERM TEDISAMIL ADMINISTRATION IN A POSTINFARCTED CANINE MODEL OF ISCHEMIC VENTRICULAR-FIBRILLATION

The electrophysiologic and antifibrillatory properties of tedisamil (K C-8857) were studied in vivo in a conscious canine model of sudden car diac death. Male mongrel dogs were anesthetized, and surgical anterior myocardial infarction was induced by a 2-h occlusion, with reperfusio n of the left anterior descending coronary artery. Three to five days after infarction, dogs were subjected to programmed electrical stimula tion (PES) to identify those at risk for ischemia-induced ventricular fibrillation. Previous studies documented that dogs with a significant anterior-wall infarction develop ventricular tachycardia in response to PES and are at an increased risk for sudden cardiac death on imposi tion of a transient ischemic event in a region remote from the infarct -related artery. PES-inducible animals were randomized to either oral placebo or oral tedisamil treatment (3 mg/kg, b,i,d for 4 days, Group 1, n = 8). Control animals received empty gelatin capsules (Group 2, n = 8). The effective refractory period and QTc interval were unchanged after 3 days of oral placebo or tedisamil dosing. Arrhythmic activity after drug administration was not observed In dogs treated with tedis amil, PES induction of ventricular tachycardia was reduced significant ly in the tedisamil-treated group (100% inducible before drug vs. 9% i nducible after drug; p < 0.05), In the sudden-cardiac-death protocol, tedisamil reduced the incidence of lethal ischemic arrhythmias develop ing in response to acute posterolateral myocardial ischemia. Tedisamil -treated animals exhibited a 100% compared with a 25% survival rate in the control group (p < 0.05). Anterior-wall infarct size, expressed a s a percentage of the left ventricle, did not differ between groups: G roup 1 = 20 +/- 1%; Group 2 = 22 +/- 1%. Our findings suggest that ted isamil might be useful in the prevention of malignant ventricular arrh ythmias in myocardial ischemic injury.