on March 26, 2007
Published online before print March 26, 2007, doi: 10.1161/CIRCULATIONAHA.106.675710
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Submitted on September 20, 2006
From the Departments of Physiology (M.V.C., X.-M.Y., J.M.D.) and Medicine (M.V.C.), University of South Alabama, College of Medicine, Mobile, Ala. * To whom correspondence should be addressed. E-mail: mcohen{at}usouthal.edu.
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/10-second 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 KATP 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.
Accepted on February 2, 2007
The pH Hypothesis of Postconditioning. Staccato Reperfusion Reintroduces Oxygen and Perpetuates Myocardial Acidosis
Michael V. Cohen MD*,
Key words: acidosis • free radicals • mitochondrial permeability transition pore • myocardial infarction • reperfusion
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