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≤0.001 versus control). The Ca2+ load required to open the mPTP averaged 41±4, 47±5, and 67±9 μmol/L CaCl2 per mg of mitochondrial proteins in postconditioning, preconditioning, and NIM811, respectively, significantly higher than the value of 16±4 μmol/L per mg in controls (P≤0.05). Conclusions - Postconditioning inhibits opening of the mPTP and provides a powerful antiischemic protection.