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1 University College Hospital and Medical School, The Hatter Institute and Centre for Cardiology, London, United Kingdom
2 University College London, Department of Physiology, The Mitochondrial Biology Group, London, United Kingdom
* To whom correspondence should be addressed. E-mail: d.yellon{at}ucl.ac.uk.
The 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 the mPT can be reliably and reproducibly induced in order 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, TMRM, which generates oxidative stress on laser illumination, so 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 to control (p<0.001) and rigor contracture by 1.5 fold compared to 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 to control (p<0.001). The effects of HP, diazoxide and nicorandil were abolished in the presence of the mitochondrial 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.
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