Dinitrophenol, cyclosporin A, and trimetazidine modulate preconditioning in the isolated rat heart: Support for a mitochondrial role in cardioprotection

Background: Recent studies have postulated that mitochondrial ATP- sensitive potassium (mitoK(ATP)) 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 mitoK(ATP) 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. (C) 2000 Elsevier Science B.V.