Suppression of lethal ischemic ventricular arrhythmias by the class III agent E4031 in a canine model of previous myocardial infarction.
The antiarrhythmic efficacy of a new and potent class III agent E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4- methylsulfonylaminobenzoyl)piperidine] was evaluated in several canine models of recent myocardial infarction. In anesthetized dogs with baseline inducible ventricular arrhythmias studied 4-10 days after anterior myocardial infarction, 30-300 micrograms/kg i.v. E4031 suppressed induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 7 of 10 animals tested, while significantly prolonging refractoriness in both noninfarcted and infarcted ventricular myocardium. The incidence of lethal ischemic ventricular arrhythmias developing in response to acute posterolateral myocardial ischemia in the presence of previous anterior infarction was reduced from 10 of 10 (100%) in a vehicle pretreatment group to 3 of 10 (30%, p less than 0.01) in an E4031 (300 micrograms/kg intravenously, i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (26.9 +/- 3.7 vs. 33.2 +/- 2.1% of left ventricle) nor the times to development of acute posterolateral myocardial ischemia (43 +/- 11 vs. 40 +/- 8 min) differed significantly between the vehicle and E4031 pretreatment groups, respectively, suggesting that the reduction in the incidence of lethal ischemic arrhythmias in the E4031 pretreatment group was not due to smaller underlying, electrically unstable myocardial substrates nor to a delay in onset of the acute ischemic insult. In conscious dogs with spontaneous ventricular ectopy at 48 h after myocardial infarction and in anesthetized dogs with no baseline inducible arrhythmias at 4-10 days after myocardial infarction, E4031 (30-3,000 micrograms/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents such as E4031 that increase ventricular refractoriness (class III electrophysiologic activity) may provide significant protection against development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction.
Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
J J
JJ
Lynch
L A
LA
Heaney
A A
AA
Wallace
J R
JR
Gehret
H G
HG
Selnick
R B
RB
Stein
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002698:Chloralose; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000502:physiology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D002698:Chloralose