Postconditioning inhibits mitochondrial permeability transition

Abstract

Background: Brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called "postconditioning." After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. We hypothesized that postconditioning may modulate mPTP opening.

Methods and results: Anesthetized open-chest rabbits underwent 30 minutes of ischemia and 4 hours of reperfusion. Control hearts underwent no additional intervention. Postconditioning consisted of 4 episodes of 1 minute of coronary occlusion and 1 minute of reperfusion performed after 1 minute of reflow after the prolonged ischemia. Preconditioning consisted of 5 minutes of ischemia and 5 minutes of reperfusion before the 30-minute ischemia. An additional group of rabbits received 5 mg/kg IV of NIM811, a specific inhibitor of the mPTP, 1 minute before reperfusion. Infarct size was assessed by triphenyltetrazolium staining. Mitochondria were isolated from the risk region myocardium, and Ca2+-induced mPTP opening was assessed by use of a potentiometric method. Postconditioning, preconditioning, and NIM811 significantly limited infarct size, which averaged 29+/-4%, 18+/-4%, and 20+/-4% of the risk region, respectively, versus 61+/-6% in controls (P< or =0.001 versus control). The Ca2+ load required to open the mPTP averaged 41+/-4, 47+/-5, and 67+/-9 micromol/L CaCl2 per mg of mitochondrial proteins in postconditioning, preconditioning, and NIM811, respectively, significantly higher than the value of 16+/-4 micromol/L per mg in controls (P< or =0.05).

Conclusions: Postconditioning inhibits opening of the mPTP and provides a powerful antiischemic protection.