Effects of BIIB513 on ischemia-induced arrhythmias and myocardial infarction in anesthetized rats.
Na+/H+ exchange (NHE) plays an important role in the regulation of the intracellular pH (pHi) and in cardiac cell injury induced by ischemia and reperfusion. In the present study, we investigated the effects of BIIB513, a selective NHE-1 inhibitor on myocardial ischemia induced arrhythmias and myocardial infarction, provoked by 30 minutes of left main coronary artery occlusion followed by 2 hours of reperfusion in an anesthetized rat model. Intravenous administration of BIIB513 (0.01-3.0 mg/kg) did not induce changes in blood pressure or heart rate. BIIB513 (0.01, 0.1, 0.3, 1.0, 3.0 mg/kg) given prior to the coronary artery occlusion dose-dependently reduced ventricular premature beats, ventricular tachycardia, and a complete suppression of ventricular fibrillation down to the dose of 0.1 mg/kg. BIIB513 (0.01, 0.1, 0.3, 1.0, 3.0 mg/kg) given prior to the coronary artery occlusion dose-dependently reduced the infarct size with an ED50 value of 0.16 mg/kg. BIIB513 (1.0 mg/kg) given prior to reperfusion also reduced infarct size by 47.3 +/- 13.1%. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase (CPK). In conclusion, the present study demonstrates the cardioprotective ability of NHE-1 inhibition during myocardial ischemia and reperfusion by reducing serious ventricular arrhythmias and myocardial infarct size in anesthetized rats.
Wu
D
D
Cardiovascular/Metabolic Research, Boehringer Ingelheim Pharma KG, Biberach, Germany.
Stassen
J M
JM
Seidler
R
R
Doods
H
H
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D003402:Creatine Kinase / Q000097:blood; D004837:Epinephrine / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008698:Mesylates / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology*; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012720:Severity of Illness Index
D008698:Mesylates; D003402:Creatine Kinase; C402725:BIIB 513; D009638:Norepinephrine; D004837:Epinephrine