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EXPERIMENTAL STUDIES

EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction

Joseph J. Lynch, Jr., PhD^*, Gary L. Stump, BS^*, Audrey A. Wallace, BS^*, Carla A. Painter, BS^*, Justina M. Thomas, BS, Sandra E. Kusma, BS, Robert J. Gould, PhD^* and William Grossman, MD, FACC^,1

^* Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA
Department of Clinical Cardiovascular Research, Merck Research Laboratories, West Point, Pennsylvania, USA

Manuscript received December 22, 1998; revised manuscript received March 19, 1999, accepted May 10, 1999.

Reprint requests and correspondence: Joseph J. Lynch, Jr., WP46-300, Merck Research Laboratories, West Point, Pennsylvania 19486., USA

OBJECTIVES

The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan’s more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction.

BACKGROUND

Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death.

METHODS

Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 ± 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment.

RESULTS

Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size.

CONCLUSIONS

EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   AI = angiotensin I   AII = angiotensin II   ANOVA = analysis of variance   ELITE = Evaluation of Losartan in the Elderly   IZ = infarct zone   LCX = left circumflex   NZ = noninfarct zone

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