Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism.
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 8x13 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 Ca2+ 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.
Research Institute, The Hospital for Sick Children and Department of Surgery, University of Toronto, 555 University Ave., Toronto, Ontario, Canada M5G 1X8.
Sandra E
SE
McAllister
Homa
H
Ashrafpour
Neil
N
Cahoon
Ning
N
Huang
Michael A
MA
Moses
Peter C
PC
Neligan
Christopher R
CR
Forrest
Joan E
JE
Lipa
Cho Y
CY
Pang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001278:Atractyloside / Q000008:administration & dosage; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage; D004195:Disease Models, Animal; D007238:Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013552:Swine; D013997:Time Factors
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001278:Atractyloside; D016572:Cyclosporine; D000255:Adenosine Triphosphate; C090438:(melle-4)cyclosporin; D009195:Peroxidase; D002118:Calcium