© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Dinitrophenol, cyclosporin A, and trimetazidine modulate preconditioning in the isolated rat heart: support for a mitochondrial role in cardioprotection
aThe Hatter Institute for Cardiology Research, Interuniversity Cape Heart Research Group of the Medical Research Council, University of Cape Town Medical School, Observatory, Cape Town 7925, South Africa
bThe Hatter Institute for Cardiovascular Studies, University College London Hospitals, Grafton Way, London WC1E 6DB, UK
cThe Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah University Hospital, Jerusalem 91120, Israel
* Corresponding author. Tel.: +27-21-406-6358; fax: +27-21-447-8789 jminners{at}samiot.uct.ac.za
Background: Recent studies have postulated that mitochondrial ATP-sensitive potassium (mitoKATP) channel activation may modulate mitochondrial function with the resultant induction of a preconditioning phenotype in the heart. We hypothesized that the modulation of mitochondrial homeostasis might confer preconditioning-like cardioprotection. Methods: We used a model of regional ischemia in Langendorff-perfused isolated rat hearts. Short-term administration of 2,4-dinitrophenol (DNP), an uncoupler of oxidative phosphorylation and cyclosporin A (CSA), an inhibitor of mitochondrial respiration, was used in an attempt to elicit preconditioning-like cardioprotection. The anti-ischemic drug trimetazidine, known to attenuate CSA-induced disruption in mitochondrial function, and the mitoKATP channel blocker 5-hydroxydecanoic acid (5-HD) were used to inhibit the effects of DNP and CSA. Finally, we studied the effect of trimetazidine on adenosine-induced and ischemic preconditioning. Risk zone and infarct size were measured and expressed as a percentage of the risk zone (I/R ratio). Results: DNP, CSA and adenosine pretreatment reduced infarct size (I/R ratio: DNP 9.0±2.4%, CSA 12.5±1.4%, adenosine 11.9±3.6%, all P<0.001 vs. control, 30.2±1.3%) similarly to ischemic preconditioning (9.5±0.6%, P<0.001 vs. control). Trimetazidine limited the effect of ischemic preconditioning (22.2±2.0%, P<0.001 vs. ischemic preconditioning) and completely reversed the DNP, CSA, and the adenosine-mediated reduction in infarct size. 5-HD abolished the effect of ischemic preconditioning and CSA. Conclusion: DNP and CSA trigger preconditioning-like cardioprotection in the isolated rat heart. Trimetazidine, a known mitochondrial ‘protector’, attenuated both drug-induced and ischemic preconditioning. These data support the hypothesis that modulation of mitochondrial homeostasis may be a common downstream cellular event linking different triggers of preconditioning.
KEYWORDS Infarction; Ischemia; K-ATP channel; Mitochondria; Oxidative phosphorylation; Preconditioning
1 J.M. and E.J.B. contributed equally to this work.
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