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Suppression of lethal ischemic ventricular arrhythmias by the class III agent E4031 in a canine model of previous myocardial infarction
J Mel Cell Cardiol21
460
(Supplement
II) (1989)
CARDIOPROTECTIVE EFFECTS OF DILAZEP ON MYOCARDIAL METABOLISM AND INFARCT SIZE IN EXPERIMENTAL MYOCARDIAL INFARCTION. Uma Singh, S.D. Seth, S.C. Manchanda. Department of Pharmacology, All India Institute of Medical Sciences, New Delhi - IIOOZY. The efficacy of d&rep, a diazepine derivative to limit the myocardial infarct size following induction of experimental acute myocardial infarction by ligating the left anterior descending (LAD) coronary artery was assessed in fourteen open chest anesthetlsed dogs. Ischemia resulted in a transmural infarct and marked metabolic changes twenty four hours post-occlusion. Dilazep (0.2 mg/kg i.v.) administred 20 min post-occlusion significantly (p
461 STUDIES
ON LEUKOTRIENE (LT) C4-METABOLIZING ENZYME IN THE RABBIT MYOCARDIUM. ENHANCED CONVERSION OF LTC4 TO LTD4 AND LTE4 IN INFARCTED MYOCARDIUM. M.Nakamura, H.Kawaguchi, H.Yasuda. Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan. Peptidyl LTs are produced in ischemic myocardium and have a profound depressant effect on myocardial contractivity and increase tissue damages. This study was performed to clarify the metabolism of LTC4 in the left ventricular myocardium and to determine the changes of that metabolism in infarcted myocardium. [3H]LTC4 was incubated with myocardial subcellular fractions and LTC4-metabolizing r-GTP activity was measured using RI?-HPLC. LTC4 was rapidly converted to LTD4 by microsomal fractions. The apparent Km value was 2.72*0.5ptEl, and Vmax was 1.49i0.27 nmol/min/mg protein. r-GTP activity was increased significantly (p
462
OF LETHAL ISCHEMIC VENTRICULAR ARRHYTHMIAS BY THE CLASS III AGENT E4031 IN A CANINE MODEL OF PREVIOUS MYOCARDIAL INFARCTION. J. Lynch, L. Heaney, A. Wallace, R. Stein. Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania., U.S.A. In anesthetized dogs studied 4-8 days after anterior myocardial infarction, 30.0-300.0 w/kg i.v. E4031 [1-[2(8-methyl-2-pyridyl)ethyl]-4-(4-methylsuIfonylaminobenzoyl)piperidine] suppressed the induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 8 of 8 (75%) animals tested, while significantly prolonging refractoriness in both non-infarcted 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 8 of 8 (I 00%) in a vehicle pretreatment group to 3 of 8 (37.5%) in an E4031 (300.0 pg/kg i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (29.7&3.5% vs 31.a2.1% of left ventricle) nor the times to the development of acute posterolateral myocardial ischemia (37.9k13.2 vs 41.9f8.3 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 due to a delay in the onset of the acute ischemic ins&. In conscious dogs with spontaneous ventricular ectopy at 48 hours after myocardial infarction and in anesthetized dogs with no baseline inducible tachyarrhythmias at 4-8 days after myocardial infarction, E4031 (30.0-3000.0 w/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents which increase ventricular refractoriness (Class Ill eiectrophysfologic activity) such as E4031 may provide significant protection against the development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction. SUPPRESSION
s.154
460
(Supplement
II) (1989)
CARDIOPROTECTIVE EFFECTS OF DILAZEP ON MYOCARDIAL METABOLISM AND INFARCT SIZE IN EXPERIMENTAL MYOCARDIAL INFARCTION. Uma Singh, S.D. Seth, S.C. Manchanda. Department of Pharmacology, All India Institute of Medical Sciences, New Delhi - IIOOZY. The efficacy of d&rep, a diazepine derivative to limit the myocardial infarct size following induction of experimental acute myocardial infarction by ligating the left anterior descending (LAD) coronary artery was assessed in fourteen open chest anesthetlsed dogs. Ischemia resulted in a transmural infarct and marked metabolic changes twenty four hours post-occlusion. Dilazep (0.2 mg/kg i.v.) administred 20 min post-occlusion significantly (p
461 STUDIES
ON LEUKOTRIENE (LT) C4-METABOLIZING ENZYME IN THE RABBIT MYOCARDIUM. ENHANCED CONVERSION OF LTC4 TO LTD4 AND LTE4 IN INFARCTED MYOCARDIUM. M.Nakamura, H.Kawaguchi, H.Yasuda. Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan. Peptidyl LTs are produced in ischemic myocardium and have a profound depressant effect on myocardial contractivity and increase tissue damages. This study was performed to clarify the metabolism of LTC4 in the left ventricular myocardium and to determine the changes of that metabolism in infarcted myocardium. [3H]LTC4 was incubated with myocardial subcellular fractions and LTC4-metabolizing r-GTP activity was measured using RI?-HPLC. LTC4 was rapidly converted to LTD4 by microsomal fractions. The apparent Km value was 2.72*0.5ptEl, and Vmax was 1.49i0.27 nmol/min/mg protein. r-GTP activity was increased significantly (p
462
OF LETHAL ISCHEMIC VENTRICULAR ARRHYTHMIAS BY THE CLASS III AGENT E4031 IN A CANINE MODEL OF PREVIOUS MYOCARDIAL INFARCTION. J. Lynch, L. Heaney, A. Wallace, R. Stein. Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania., U.S.A. In anesthetized dogs studied 4-8 days after anterior myocardial infarction, 30.0-300.0 w/kg i.v. E4031 [1-[2(8-methyl-2-pyridyl)ethyl]-4-(4-methylsuIfonylaminobenzoyl)piperidine] suppressed the induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 8 of 8 (75%) animals tested, while significantly prolonging refractoriness in both non-infarcted 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 8 of 8 (I 00%) in a vehicle pretreatment group to 3 of 8 (37.5%) in an E4031 (300.0 pg/kg i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (29.7&3.5% vs 31.a2.1% of left ventricle) nor the times to the development of acute posterolateral myocardial ischemia (37.9k13.2 vs 41.9f8.3 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 due to a delay in the onset of the acute ischemic ins&. In conscious dogs with spontaneous ventricular ectopy at 48 hours after myocardial infarction and in anesthetized dogs with no baseline inducible tachyarrhythmias at 4-8 days after myocardial infarction, E4031 (30.0-3000.0 w/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents which increase ventricular refractoriness (Class Ill eiectrophysfologic activity) such as E4031 may provide significant protection against the development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction. SUPPRESSION
s.154