Abstract | OBJECTIVES: 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.
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Authors | J J Lynch Jr, G L Stump, A A Wallace, C A Painter, J M Thomas, S E Kusma, R J Gould, W Grossman |
Journal | Journal of the American College of Cardiology
(J Am Coll Cardiol)
Vol. 34
Issue 3
Pg. 876-84
(Sep 1999)
ISSN: 0735-1097 [Print] United States |
PMID | 10483973
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Angiotensin-Converting Enzyme Inhibitors
- Anti-Arrhythmia Agents
- Imidazoles
- Tetrazoles
- Angiotensin II
- Captopril
- losartan carboxylic acid
- Losartan
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Topics |
- Analysis of Variance
- Angiotensin II
(antagonists & inhibitors)
- Angiotensin-Converting Enzyme Inhibitors
(therapeutic use)
- Animals
- Anti-Arrhythmia Agents
(therapeutic use)
- Arrhythmias, Cardiac
(etiology, prevention & control)
- Captopril
(therapeutic use)
- Disease Models, Animal
- Dogs
- Drug Evaluation, Preclinical
- Female
- Heart Ventricles
- Humans
- Imidazoles
(therapeutic use)
- Losartan
(therapeutic use)
- Male
- Myocardial Infarction
(complications)
- Myocardial Ischemia
(etiology, prevention & control)
- Tetrazoles
(therapeutic use)
- Time Factors
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