Protective effect of FR183998, a Na+/H+ exchange inhibitor, against postischemic injury after normothermic and prolonged hypothermic ischemia in isolated perfused rat hearts.
Inhibition of Na+/H+ exchanger has been reported to protect hearts from ischemia and reperfusion injury. However, the effect of Na+/H+ exchange inhibition on hypothermic ischemic injury has not been extensively studied and the results are inconsistent. The purpose of this study was to investigate whether inhibition of Na+/H+ exchange with FR183998 (5-(2,5-dichlorothiphen-3-yl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoylguanidine dihydrochloride), a potent Na+/H+ exchange inhibitor, would show protective effects against postischemic cardiac dysfunction after hypothermic as well as normothermic ischemia and furthermore, after hypothermic cardioplegic arrest in isolated rat hearts. FR183998 (3.2 x 10(-8)-3.2 x 10(-7) M) improved post-ischemic recovery of left ventricular developed pressure and suppressed the increase of left ventricular end diastolic pressure in a dose-dependent manner, after not only 45 min of normothermic ischemia but also 6 h of hypothermic ischemia. Furthermore, FRI 83998 (10(-7)-10(-6) M) significantly reduced creatine kinase release during reperfusion after 3 h of hypothermic ischemia with cardioplegia. These results indicate that FR183998 has a potent protective effect on postischemic cardiac dysfunction after normothermic and hypothermic ischemia, and also on reperfusion injury after hypothermic cardioplegic arrest, suggesting that its effect would be additive to cardioplegia.
Ohara
F
F
Department of Cardiovascular Diseases, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan. fumihiro_ohara@po.fujisawa.co.jp
Yamamoto
N
N
Maeda
K
K
Ozaki
T
T
Seki
J
J
Goto
T
T
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003080:Cold Temperature; D003402:Creatine Kinase / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006324:Heart Arrest, Induced / Q000009:adverse effects; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D002316:Cardiotonic Agents; C449400:FR 183998; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; D003402:Creatine Kinase