Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury.
The aim of the present study was to determine whether specific inhibition of mitochondrial permeability transition (MPT) by NIM811 at the time of reperfusion following acute myocardial infarction may protect the heart. MPT pore opening appears to be a pivotal event in cell death following acute myocardial infarction. Recently, MPT pore opening has been involved in ischemic preconditioning. In protocol 1, NZW rabbits underwent either no intervention (sham) or 10 min of ischemia followed by 5 min of reperfusion, preceded (preconditioned, PC) or not (control, C) by 5 min of ischemia and 5 min of reperfusion. Additional rabbits were treated by cyclosporin A (CsA) or its non-immunosuppressive and more specific derivative (NIM811) (10 mg kg(-1), IV bolus), either 10 min before ischemia or 1 min before reperfusion. Hearts were excised and mitochondria isolated for further assessment of Ca(2+)-induced MPT. In protocol 2, animals were randomly assigned into similar experimental groups and underwent 30 min of ischemia and 4 h of reperfusion. Infarct size was assessed by TTC staining, and apoptosis by TUNEL assay. The Ca2+ overload required to induce MPT pore opening was significantly higher in NIM811, CsA and PC groups than in controls. Both necrotic and apoptotic cardiomyocyte death were significantly reduced by NIM811, CsA and PC. In both protocols, administration of NIM811 at reperfusion provided full protection. These data indicate that specific inhibition of MPT pore opening at reperfusion following acute myocardial infarction provides a powerful antinecrotic and antiapoptotic protection.
Argaud
Laurent
L
Inserm E 0226, Laboratoire de Physiologie Lyon-Nord, Faculté de Médecine Lyon-Nord, Université Claude Bernard Lyon I, 8, avenue Rockefeller, 69373 Lyon cedex 8, France.
Gateau-Roesch
Odile
O
Muntean
Danina
D
Chalabreysse
Lara
L
Loufouat
Joseph
J
Robert
Dominique
D
Ovize
Michel
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007425:Intracellular Membranes / Q000187:drug effects*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D010539:Permeability / Q000187:drug effects*; D011817:Rabbits
D002316:Cardiotonic Agents; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D002118:Calcium