The pH hypothesis of postconditioning - Staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis
The pH hypothesis of postconditioning - Staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis
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DOI：
10.1161/circulationaha.106.675710
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发表时间：
2007-04-10
期刊：
影响因子：
37.8
通讯作者：
Downey, James M.
中科院分区：
文献类型：
--
作者：
Cohen, Michael V.;Yang, Xi-Ming;Downey, James M.
背景-目前尚不清楚冠状动脉再灌注/闭塞交替循环的梗死心脏再灌注如何减轻梗死，但预防线粒体通透性转换孔（MPTP）的形成是至关重要的。酸中毒也抑制MPTP的形成。我们测试了后处理是否通过在早期复氧期间维持酸中毒来保护。方法和结果-在离体兔心脏局部缺血30分钟后，用缓冲液再灌注（pH 7.4）导致34.4 +/- 2.2%的风险区梗死，而再灌注时2分钟的后处理（6个循环的10秒再灌注/10秒闭塞）导致10.7 +/-2.9%的梗死。1分钟（3个循环）的后处理没有保护作用。高碳酸缓冲液（pH 6.9）在再灌注的前2分钟代替后处理引起了等效的心脏保护（15.0 +/- 2.6%梗死），而1分钟的酸中毒没有保护作用。延迟后处理（6个周期）或2分钟酸中毒1分钟中止保护。再灌注缓冲液（pH 7.7）阻断后处理的保护，但除了MPTP更接近环孢菌素A恢复保护。活性氧清除剂N-2-巯基丙酰甘氨酸、蛋白激酶C拮抗剂白屈菜红碱和线粒体K-ATP通道封闭剂5-羟基癸酸盐各自阻断了2分钟酸中毒的保护作用，就像它们在后处理中所做的那样。后处理通过在再灌注的最初几分钟内维持酸中毒来防止MPTP的形成，因为再氧合的心肌产生活性氧物质，活性氧物质激活保护性信号，抑制pH正常化后MPTP的形成。
Background - It is unclear how reperfusion of infarcting hearts with alternating cycles of coronary reperfusion/occlusion attenuates infarction, but prevention of mitochondrial permeability transition pore (MPTP) formation is crucial. Acidosis also suppresses MPTP formation. We tested whether postconditioning protects by maintaining acidosis during early reoxygenation.Methods and Results - After 30-minute regional ischemia in isolated rabbit hearts, reperfusion with buffer (pH 7.4) caused 34.4 +/- 2.2% of the risk zone to infarct, whereas 2 minutes of postconditioning (6 cycles of 10-second reperfusion/10second occlusion) at reperfusion resulted in 10.7 +/- 2.9% infarction. One minute (3 cycles) of postconditioning was not protective. Hypercapnic buffer (pH 6.9) for the first 2 minutes of reperfusion in lieu of postconditioning caused equivalent cardioprotection (15.0 +/- 2.6% infarction), whereas 1 minute of acidosis did not protect. Delaying postconditioning (6 cycles) or 2 minutes of acidosis for 1 minute aborted protection. Reperfusion with buffer (pH 7.7) blocked postconditioning protection, but addition of the MPTP closer cyclosporin A restored protection. Reactive oxygen species scavenger N-2-mercaptopropionyl glycine, protein kinase C antagonist chelerythrine, and mitochondrial K-ATP channel closer 5-hydroxydecanoate each blocked protection from 2 minutes of acidosis as they did for postconditioning.Conclusion - Thus, postconditioning prevents MPTP formation by maintaining acidosis during the first minutes of reperfusion as reoxygenated myocardium produces reactive oxygen species that activate protective signaling to inhibit MPTP formation after pH normalization.