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Am J Physiol Heart Circ Physiol 287: H841-H849, 2004. First published April 8, 2004; doi:10.1152/ajpheart.00678.2003
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Preconditioning protects by inhibiting the mitochondrial permeability transition

Derek J. Hausenloy,1 Derek M. Yellon,1 Siva Mani-Babu,1 and Michael R. Duchen2

1The Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, London WC1E 6DB; and 2The Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom

Submitted 16 July 2003 ; accepted in final form 5 April 2004

Mitochondrial permeability transition (mPT) is a crucial event in the progression to cell death in the setting of ischemia-reperfusion. We have used a model system in which mPT can be reliably and reproducibly induced to test the hypothesis that the profound protection associated with the phenomenon of myocardial preconditioning is mediated by suppression of the mPT. Adult rat myocytes were loaded with the fluorescent probe tetramethylrhodamine methyl ester, which generates oxidative stress on laser illumination, thus inducing the mPT (indicated by collapse of the mitochondrial membrane potential) and ATP depletion, seen as rigor contracture. The known inhibitors of the mPT, cyclosporin A (0.2 µM) and N-methyl-4-valine-cyclosporin A (0.4 µM), increased the time taken to induce the mPT by 1.8- and 2.9-fold, respectively, compared with control (P < 0.001) and rigor contracture by 1.5-fold compared with control (P < 0.001). Hypoxic preconditioning (HP) and pharmacological preconditioning, using diazoxide (30 µM) or nicorandil (100 µM), also increased the time taken to induce the mPT by 2.0-, 2.1-, and 1.5-fold, respectively (P < 0.001), and rigor contracture by 1.9-, 1.7-, and 1.5-fold, respectively, compared with control (P < 0.001). Effects of HP, diazoxide, and nicorandil were abolished in the presence of mitochondrial ATP-sensitive K+ (KATP) channel blockers glibenclamide (10 µM) and 5-hydroxydecanoate (100 µM) but were maintained in the presence of the sarcolemmal KATP channel blocker HMR-1098 (10 µM). In conclusion, preconditioning protects the myocardium by reducing the probability of the mPT, which normally occurs during ischemia-reperfusion in response to oxidative stress.

ischemia-reperfusion; myocardial preconditioning; oxidative stress


Address for reprint requests and other correspondence: D. M. Yellon, The Hatter Institute and Centre for Cardiology, Univ. College London Hospitals and Medical School, Grafton Way, London WC1E 6DB, UK (E-mail: hatter-institute{at}ucl.ac.uk).




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