Antiarrhythmic and Electrophysiologic Actions of CK-357 and Sematilide in a Conscious Canine Model of Sudden Coronary Death

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Abstract
The antiarrhythmic and antifibrillatory actions of the CK-3579 and sematilide, two new class III antiarrhythmic drugs, administered in a multiple-dose regimen were evaluated in conscious dogs 3–5 days after anterior myocardial infarction. The study population consisted of three groups of 10 dogs each, in which all animals entered into the final protocol developed nonsustained or sustained ventricular tachycardia in response to programmed electrical stimulation using one, two or three premature stimuli. Each drug was administered intravenously in a dose of 3.0 mg/kg every 3 h for a total of six doses. Sematilide significantly suppressed the induction of ventricular tachyarrhythmia by programmed electrical stimulation in six of 10 postinfarcted dogs, whereas CK-3579 suppressed the induction of tachyarrhythmia in only two of 10 animals. Despite its ineffectiveness in preventing electrical induction of tachycardia, CK-3579 produced a significant increase in the cycle length of the induced ventricular rhythm. The administration of each drug was associated with an increase in the ventricular refractoriness and in the paced QT interval, suggesting that class III electrophysiologic properties contribute to the antiarrhythmic action of each drug. In addition, CK-3579 was shown to have β1-adrenoceptor blocking properties. The subsequent induction of an acute ischemic event in a region remote from the infarct-related artery was associated with a high incidence (80%, eight of 10 postinfarcted dogs) of ventricular fibrillation within the first hour after the onset of myocardial ischemia in the vehicle-treated control group. Both CK-3579 and sematilide provided a significant degree of protection (80 and 70% survival, respectively) against the development of sudden death due to ventricular fibrillation, as well as cumulative mortality determined at 24 h. The data suggest that both CK-3579 and sematilide induce cardiac electrophysiologic changes characteristic of drugs which are classified as class III antiarrhythmic agents. The most striking property of each drug appears to be related to the prevention of ventricular fibrillation as assessed in an experimental model of sudden death associated with the superimposition of an ischemic event in a region remote from a previous myocardial infarct.