The electrophysiologic and antifibrillatory properties of
tedisamil (KC-8857) were studied in vivo in a conscious canine model of
sudden cardiac death. Male mongrel dogs were anesthetized, and surgical anterior
myocardial infarction was induced by a 2-h occlusion, with reperfusion of the left anterior descending coronary artery. Three to five days after
infarction, dogs were subjected to programmed electrical stimulation (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 imposition 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
tedisamil. PES induction of
ventricular tachycardia was reduced significantly in the
tedisamil-treated group (100% inducible before
drug vs. 9% inducible after
drug; p < 0.05). In the
sudden-cardiac-death protocol,
tedisamil reduced the incidence of lethal ischemic arrhythmias developing 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 as a percentage of the left ventricle, did not differ between groups: Group 1 = 20 +/- 1%; Group 2 = 22 +/- 1%. Our findings suggest that
tedisamil might be useful in the prevention of malignant ventricular arrhythmias in myocardial ischemic injury.