© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
The cardioprotective and mitochondrial depolarising properties of exogenous nitric oxide in mouse heart
The Hatter Institute for Cardiovascular Studies, University College Hospitals and Medical School, University College, London, London WC1E 6DB, UK
hatter-institute{at}ucl.ac.uk
* Corresponding author.: Tel.: +44-20-7380-9888; fax: +44-20-7388-5095.
Objective: Nitric oxide (NO) is reported to be both protective and detrimental in models of myocardial ischaemia/reperfusion injury, which may be concentration dependent. Our objective was to characterise this dichotomy using the nitric oxide donor, S-nitroso N-acetyl penicillamine (SNAP) in isolated perfused mouse heart and isolated mouse cardiac mitochondria. Methods: To determine the effect of nitric oxide concentration on myocardial viability, isolated mouse hearts were subjected to 35 min global ischaemia and 30 min reperfusion in the presence of SNAP (0.02–20 µM). To determine whether NO mediated protection was via opening of the putative mitochondrial KATP channel and/or free radical synthesis, SNAP perfused hearts were also treated with the mitochondrial KATP channel blocker, 5-hydroxy decanoate (5-HD) and the free-radical scavenger, N-(2-mercaptopropionyl)-glycine (MPG). This data was correlated with mitochondrial membrane potential (
m), measured with the potentiometric dye, tetra-methyl rhodium methyl ester (TMRM), in isolated mitochondria,by flow cytometry. Results: SNAP dose-dependently attenuated infarct size, with maximal protection observed at 2 µM (17±4% versus controls 32±3%, P<0.01). At greater concentrations however, protection was lost with infarct sizes tending towards control at 20 µM (29±3%). These results were paralleled by changes in m in the isolated mitochondria: m depolarisation peaking with 1 µM SNAP (26±4% shift in TMRM fluorescence, P<0.01); at greater concentrations, this relationship was lost. The mitochondrial KATP channel blocker, 5-HD, resulted in both abrogation of SNAP infarct size reduction and concomitant loss of m depolarisation in the mitochondria. MPG however did not influence the cardioprotective properties of SNAP. Conclusion: We demonstrate that nitric oxide can mediate cardioprotection in a dose-dependent fashion by an effect that may be related to m. Both cardioprotection and m changes are sensitive to 5-HD and the cardioprotection appears independent of free-radical synthesis.
KEYWORDS Free radicals; Infarction; K-ATP channel; Mitochondria; Nitric oxide
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