Infarct size limitation by a new Na(+)-H+ exchange inhibitor, Hoe 642: difference from preconditioning in the role of protein kinase C

Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. miura@sapmed.ac.jp

OBJECTIVES: This study examined the effect of a new specific Na(+)-H+ exchange inhibitor, Hoe 642, on infarct size and the protective role of protein kinase C (PKC) by this agent. In addition, we assessed the possible alteration of Hoe 642-induced cardioprotection by commonly used animal anesthetic drugs. BACKGROUND: Earlier studies on the contribution of Na(+)-H+ exchange to ischemic injury were complicated by nonspecific actions of the Na(+)-H+ exchange inhibitors, and the role of this exchanger in myocardial infarction in vivo remains unclear. The difference in anesthetic agents used in experiments could have resulted in discrepant findings regarding cardioprotection of some interventions, such as preconditioning and adenosine triphosphate-sensitive potassium channel openers. METHODS: Infarction was induced by 30 min of coronary occlusion and 3 h of reperfusion in the rabbit heart. In the first series of experiments, rabbits were anesthetized with pentobarbital or ketamine/xylazine. Hoe 642 was injected intravenously 10 min before ischemia or 5 min 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 reperfusion plus polyB or preconditioning alone before 30 min of ischemia. RESULTS: In pentobarbital-anesthetized rabbits, 0.3 mg/kg and 0.6 mg/kg of Hoe 642 given before ischemia limited infarct size (as percent area at risk [%IS/AR]) to 42.7 +/- 4.4% (SEM) and 26.2 +/- 5.4%, respectively, from the control value of 55.1 +/- 3.5%. However, injection of Hoe 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 size limitation by the preischemic treatment with Hoe 642 was similarly observed in the rabbits anesthetized with ketamine/xylazine. In the polyB-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 polyB (%IS/AR was 39.3 +/- 6.1% with polyB and 11.3 +/- 2.4% without polyB). CONCLUSIONS: Hoe 642 enhanced myocardial tolerance against infarction, and this enhanced tolerance was not influenced by anesthetic agents 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 PKC mediated and thus may be unrelated to preconditioning.

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