Effects of KR-32570, a new sodium hydrogen exchanger inhibitor, on myocardial infarction and arrhythmias induced by ischemia and reperfusion.
The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) in rat and dog models of coronary artery occlusion and reperfusion. In addition, we sought to clarify the efficacy of KR-32570 on reperfusion-induced fatal ventricular arrhythmia. In anesthetized rats subjected to 45-min coronary occlusion and 90-min reperfusion, KR-32570 (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 50.7%, 35.3%, 33.5% and 27.0% for 0.03, 0.1, 0.3 and 1.0 mg/kg, respectively (P<0.05). In anesthetized beagle dogs that underwent 1.2-h occlusion followed by 3.0-h reperfusion, KR-32570 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 28.9% in vehicle-treated group to 8.0% (P<0.05), and reduced the reperfusion-induced release in creatine kinase isoenzyme MB, lactate dehydrogenase, Troponin-I and glutamic-oxaloacetic transaminase. KR-32570 dose-dependently decreased the incidence of premature ventricular contraction, ventricular tachycardia or ventricular fibrillation induced by ischemia and reperfusion in rats. Similar results were obtained in dogs with reperfusion-induced arrhythmia. In separate experiments to assess the effects of timing of treatment, KR-32570 given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (40.9% and 46.1%, respectively) compared with vehicle-treated group. In all studies, KR-32570 caused no significant changes in any hemodynamic profiles. Taken together, these results indicate that KR-32570 significantly reduced the myocardial infarction and incidence of arrhythmias induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles. Thus, it could be potentially useful in the prevention and treatment of myocardial injuries and lethal ventricular arrhythmias.
Lee
Byung Ho
BH
Medicinal Science Division, Korea Research Institute of Chemical Technology, Yusong, Daejon, 305-343, Republic of Korea. bhlee@krict.re.kr
Yi
Kyu Yang
KY
Lee
Sunkyung
S
Lee
Sunghou
S
Yoo
Sung-eun
SE
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D052279:Creatine Kinase, MB Form / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D017180:Tachycardia, Ventricular / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D019210:Troponin I / Q000097:blood; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control
D002316:Cardiotonic Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D019210:Troponin I; C069139:growth factor-activatable Na-H exchanger NHE-1; C502305:(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine; D007770:L-Lactate Dehydrogenase; D052279:Creatine Kinase, MB Form