Original article Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury Laurent Argaud a,b , Odile Gateau-Roesch a , Danina Muntean a , Lara Chalabreysse a , Joseph Loufouat a , Dominique Robert b , Michel Ovize a, * a 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 b Département d’Urgence et de Réanimation Médicale, Hôpital Edouard Herriot, Hospices Civils de Lyon, 5, place d’Arsonval, 69437 Lyon cedex 3, France Received 13 October 2004; received in revised form 25 November 2004; accepted 3 December 2004 Available online 26 January 2005 Abstract 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 reperfu- sion. 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 Ca 2+ 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. © 2005 Elsevier Ltd. All rights reserved. Keywords: Preconditioning; Cyclosporin A; NIM811; Ischemia; Reperfusion 1. Introduction There is no doubt that reperfusion limits irreversible injury following a prolonged ischemic insult, and reperfusion strat- egies have been extensively studied and developed in clinical practice over the last two decades [1,2]. Reperfusion has also been named a “double-edged sword”, since it is associated with reversible functional alterations including myocardial stunning, arrhythmias or no-reflow [3]. The existence of another form of reperfusion, namely lethal reperfusion injury, has been widely investigated and remains a matter of debate [4,5]. Demonstration of the existence of lethal reperfusion injury would imply reduction of infarct size following admin- istration of a pharmacological agent at the time of reperfu- sion. Recently, the demonstration that several peptide growth factors as well as caspase inhibitors can attenuate myocardial cell death when administered at the time of reflow, reacti- vated the issue of lethal reperfusion injury and the hope for the development of adjunctive treatments to thrombolysis or coronary angioplasty during acute myocardial infarction [6–9]. It has been recently demonstrated that brief episodes of ischemia–reperfusion performed at the time of reflow (named “postconditioning”) may similarly attenuate lethal reperfusion injury, likewise the previously described con- trolled reperfusion [10–12]. In the past 3 years, increasing research has been focused on the role of mitochondrial permeability transition (MPT) * Corresponding author. Tel.: +33-4-78-77-70-74; fax: +33-4-78-77-71-75. E-mail address: ovize@rockefeller.univ-lyon1.fr (M. Ovize). Journal of Molecular and Cellular Cardiology 38 (2005) 367–374 www.elsevier.com/locate/yjmcc 0022-2828/$ - see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2004.12.001