Antiarrhythmic and electrophysiologic actions of CK-3579 and sematilide in a conscious canine model of sudden coronary death.
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 beta 1-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.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
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Driscoll
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Lucchesi
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D000319:Adrenergic beta-Antagonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D003645:Death, Sudden; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography; D006321:Heart / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D011342:Procainamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D011412:Propanolamines; C062818:sematilide; C063532:ersentilide; D011342:Procainamide