Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2008-08, Vol.295 (2), p.R681-R689
• Main Authors: McAllister, Sandra E, Ashrafpour, Homa, Cahoon, Neil, Huang, Ning, Moses, Michael A, Neligan, Peter C, Forrest, Christopher R, Lipa, Joan E, Pang, Cho Y
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Atractyloside - administration & dosage; Calcium; Calcium - metabolism; Cyclosporine - administration & dosage; Disease Models, Animal; Hogs; Infarction - metabolism; Infarction - pathology; Infarction - prevention & control; Injections, Intravenous; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Muscle, Skeletal - blood supply; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Musculoskeletal system; Peroxidase - metabolism; Protein synthesis; Proteins; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Swine; Time Factors; Tissues
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.90303.2008

1 Research Institute, The Hospital for Sick Children and Departments of 2 Surgery and 3 Physiology, University of Toronto, Toronto, Ontario, Canada; and 4 Department of Surgery, University of Washington, Seattle, Washington Submitted 20 March 2008 ; accepted in final form 26 May 2008 We tested our hypothesis that postischemic conditioning (PostC) is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mitochondrial permeability transition pore (mPTP). In bilateral 8 x 13 cm pig latissimus dorsi muscle flaps subjected to 4 h ischemia, muscle infarction increased from 22 ± 4 to 41 ± 1% between 2 and 24 h reperfusion and remained unchanged at 48 (38 ± 6%) and 72 (40 ± 1%) h reperfusion ( P < 0.05; n = 4 pigs). PostC induced by four cycles of 30-s reperfusion/reocclusion at the onset of reperfusion after 4 h ischemia reduced muscle infarction from 44 ± 2 to 22 ± 2% at 48 h reperfusion. This infarct protective effect of PostC was mimicked by intravenous injection of the mPTP opening inhibitor cyclosporin A or NIM-811 (10 mg/kg) at 5 min before the end of 4 h ischemia and was abolished by intravenous injection of the mPTP opener atractyloside (10 mg/kg) at 5 min before PostC ( P < 0.05; n = 4–5 pigs). PostC or intravenous cyclosporin A injection at 5 min before reperfusion caused a decrease in muscle myeloperoxidase activity and mitochondrial free Ca 2+ concentration and an increase in muscle ATP content after 4 h ischemia and 2 h reperfusion compared with the time-matched controls. These effects of PostC were abolished by intravenous injection of atractyloside at 5 min before PostC ( P < 0.05; n = 6 pigs). These observations support our hypothesis that PostC is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mPTP. skeletal muscle postconditioning; mitochondrial permeability transition pore; neutrophil accumulation; mitochondrial calcium content; 5'-adenosine triphosphate synthesis Address for reprint requests and other correspondence: C. Y. Pang, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8 (e-mail: pang{at}sickkids.ca )