title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: G L
authors.initials: GL
authors.lastname: Stump
authors.forename: A A
authors.initials: AA
authors.lastname: Wallace
authors.forename: C A
authors.initials: CA
authors.lastname: Painter
authors.forename: J M
authors.initials: JM
authors.lastname: Thomas
authors.forename: S E
authors.initials: SE
authors.lastname: Kusma
authors.forename: R J
authors.initials: RJ
authors.lastname: Gould
authors.forename: W
authors.initials: W
authors.lastname: Grossman
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D002216:Captopril / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D017202:Myocardial Ischemia / Q000209:etiology / Q000517:prevention & control*; D013777:Tetrazoles / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D002216:Captopril; C066026:losartan carboxylic acid; D019808:Losartan