INFARCT SIZE LIMITATION BY A NEW NA-H+ EXCHANGE INHIBITOR, HOE-642 - DIFFERENCE FROM PRECONDITIONING IN THE ROLE OF PROTEIN-KINASE-C()

Objectives. This study examined the effect of a new specific Na+-H+ ex change inhibitor, Hoe 642, on infarct size and the protective role of protein kinase C (PKC) by this agent. In addition, we assessed the pos sible alteration of Hoe 642-induced cardioprotection by commonly used animal anesthetic drugs. Background. Earlier studies on the contributi on of Na+-H+ exchange to ischemic injury were complicated by nonspecif ic actions of the Na+-H+ exchange inhibitors, and the role of this exc hanger in myocardial infarction in vivo remains unclear. The differenc e in anesthetic agents used in experiments could have resulted in disc repant findings regarding cardioprotection of some interventions, such as preconditioning and adenosine triphosphate-sensitive potassium cha nnel openers. Methods. Infarction was induced by 30 min of coronary oc clusion and 3 h of reperfusion in the rabbit heart. In the first serie s of experiments, rabbits were anesthetized with pentobarbital or keta mine/xylazine. Hoe 642 was injected intravenously 10 min before ischem ia or 5 ruin before reperfusion. In the second series of experiments, rabbits received 25 mg/kg body weight of polymyxin B (polyB), Hoe 642 plus polyB, preconditioning with 5 min of ischemia and 5 min of reperf usion plus polyB or preconditioning alone before 30 min of ischemia. R esults. In pentobarbital-anesthetized rabbits, 0.3 mg/kg and 0.6 mg/kg of Hoe 642 given before ischemia limited infarct size (as percent are a at risk [%IS/AR]) to 42.7 +/- 4.4% (SEM) and 26.2 +/- 5.4%, respecti vely, from the control value of 55.1 +/- 3.5%. However, injection of H oe 642 before reperfusion did not change infarct size (%IS/AR 49.6 +/- 4.9%, p = 0.387; power 0.81 for detecting 50% reduction). Infarct siz e limitation by the preischemic treatment with Hoe 642 was similarly o bserved in the rabbits anesthetized with ketamine/xylazine. In the pol yB-treated rabbits, 0.6 mg/kg of Hoe 642 significantly limited infarct size (%IS/AR was 28.3 +/- 3.8% with Hoe 642 and 50.1 +/- 7.5% without Hoe 642), although preconditioning was blocked by the same dose of po lyB (%IS/AR was 39.3 +/- 6.1% with polyB and 11.3 +/- 2.4% without pol yB). Conclusions. Hoe 642 enhanced myocardial tolerance against infarc tion, and this enhanced tolerance was not influenced by anesthetic age nts commonly used for infarct size studies. Infarct size limitation by Hoe 642 was not inhibited by polyB, suggesting that cardioprotection by Na+-H+ exchange inhibition is not PRC mediated and thus may be unre lated to preconditioning. (C) 1997 by the American College of Cardiolo gy.