Miura T, Ogawa T, Suzuki K, Goto M, Shimamoto K
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
J Am Coll Cardiol. 1997 Mar 1;29(3):693-701. doi: 10.1016/s0735-1097(96)00522-0.
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.
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.
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.
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).
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.
本研究检测了新型特异性钠氢交换抑制剂Hoe 642对梗死面积的影响以及该药物对蛋白激酶C（PKC）的保护作用。此外，我们评估了常用动物麻醉药物对Hoe 642诱导的心脏保护作用可能产生的改变。
早期关于钠氢交换对缺血性损伤作用的研究因钠氢交换抑制剂的非特异性作用而变得复杂，该交换体在体内心肌梗死中的作用仍不清楚。实验中使用的麻醉剂差异可能导致关于某些干预措施（如预处理和三磷酸腺苷敏感性钾通道开放剂）心脏保护作用的研究结果存在差异。
通过在兔心脏中进行30分钟冠状动脉闭塞和3小时再灌注诱导梗死。在第一组实验中，兔子用戊巴比妥或氯胺酮/赛拉嗪麻醉。在缺血前10分钟或再灌注前5分钟静脉注射Hoe 642。在第二组实验中，兔子接受25mg/kg体重的多粘菌素B（多粘菌素B）、Hoe 642加多粘菌素B、5分钟缺血和5分钟再灌注加多粘菌素B预处理或仅在30分钟缺血前进行预处理。
在戊巴比妥麻醉的兔子中，缺血前给予0.3mg/kg和0.6mg/kg的Hoe 642将梗死面积（作为危险区域面积的百分比[%IS/AR]）分别从对照值55.1±3.5%限制到42.7±4.4%（SEM）和26.2±5.4%。然而，再灌注前注射Hoe 642并未改变梗死面积（%IS/AR 49.6±4.9%，p = 0.387；检测50%降低的效能为0.81）。在用氯胺酮/赛拉嗪麻醉的兔子中，同样观察到缺血前用Hoe 642治疗可限制梗死面积。在多粘菌素B治疗的兔子中，0.6mg/kg的Hoe 642显著限制了梗死面积（使用Hoe 642时%IS/AR为28.3±3.8%，未使用Hoe 642时为50.1±7.5%），尽管相同剂量的多粘菌素B阻断了预处理（使用多粘菌素B时%IS/AR为39.3±6.1%，未使用多粘菌素B时为11.3±2.4%）。
Hoe 642增强了心肌对梗死的耐受性，且这种增强的耐受性不受梗死面积研究中常用麻醉剂的影响。Hoe 642对梗死面积的限制未被多粘菌素B抑制，这表明钠氢交换抑制介导的心脏保护作用不是由PKC介导的，因此可能与预处理无关。
