Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on ischemia and reperfusion-induced myocardial infarction in rats and dogs.
The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P < 0.05). In anesthetized beagle dogs that underwent a 1.0-h occlusion followed by a 3.0-h reperfusion, KR-33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle-treated group to 16.4% (P < 0.05), and reduced the reperfusion-induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin-I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR-33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle-treated group. In all studies, KR-33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR-33028 (30 mum), which was added to the heart preservation solution (histidin-tryptophan-ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dt(max) after reperfusion. Taken together, these results indicate that KR-33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.
Oh
Kwang-Seok
KS
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, 100, Jangdong, Yuseong, Daejeon 305-343, Korea.
Seo
Ho Won
HW
Yi
Kyu Yang
KY
Lee
Sunkyung
S
Yoo
Sung-eun
SE
Lee
Byung Ho
BH
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D004285:Dogs; D006146:Guanidines / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D019210:Troponin I / Q000378:metabolism
D002316:Cardiotonic Agents; D006146:Guanidines; C507425:N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; D019210:Troponin I; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase