Abstract 1419: Ischemic Postconditioning Against Ischemia/Reperfusion Injury Beyond the Myocardium
In trauma surgery, skeletal muscle is subjected to sustained ischemia before surgery and ischemia/reperfusion (I/R) injury is a common complication. We tested the hypothesis that postconditioning (PostC) skeletal muscle with 4 cycles of 30 sec I/R at the beginning of reperfusion salvages ischemic skeletal muscle from I/R injury (infarction), and the mechanism involves inhibition of mitochondrial permeability pores (mPTPs). Pigs (~18 kg) with bilateral latissimus dorsi muscle flaps were assigned to 6 groups (n =5) to undergo 4h ischemia/48h reperfusion with the following treatments:
PostC muscle flaps at the beginning of reperfusion;
intravenous (IV) injection of the mPTP inhibitor NIM-811 (10 mg/kg) 5 min before reperfusion;
IV injection of the mPTP inhibitor cyclosporin A (CsA, 10 mg/kg) 5 min before reperfusion;
IV injection of the mPTP opener atractyloside (ATS, 5 mg/kg) 5 min before PostC; and
IV injection of ATS (5 mg/kg) 5 min before reperfusion.
Muscle infarction was 46 ± 2% after 4h ischemia/48h reperfusion. Muscle infarction was reduced (p < 0.05) by PostC, NIM-811 and CsA to 21 ± 1, 26 ± 2, and 27 ± 1%, respectively when given at the beginning of reperfusion. ATS abolished the infarct protection of PostC, but alone it did not induce infarction. Muscle free mitochondrial Ca2+ concentration (m[Ca2+]), ATP contents and myeloperoxidase (MPO) activity were similar in all groups before and after 4h of ischemia. At the end of 2h of reperfusion, the muscle free m[Ca2+] were lower (p < 0.05) in the PostC and CsA treatment groups than in the control (372 ± 55, 379 ± 43 and 538 ± 41 mmol/mg mitochondrial protein, respectively); muscle ATP contents were higher (p < 0.05) in PostC and CsA groups than in the control (19 ± 4, 19 ± 3, and 8 ± 1 umol/g protein, respectively); and MPO activities were lower (p < 0.05) in the PostC and CsA groups than the control (0.8 ± 0.3, 0.9 ± 0.3 and 2.1 ± 0.3 U/g wet wt., respectively). This is the first report that the efficacy and mechanism of PostC in salvage of ischemic skeletal muscle from infarction are similar to those of ischemic cardiac muscle reported by others. Importantly, our findings provide insights into the use of the clinical mPTP inhibitor CsA for salvage of ischemic skeletal muscle from I/R injury in trauma surgery.