title: Dinitrophenol, cyclosporin A, and trimetazidine modulate preconditioning in the isolated rat heart: support for a mitochondrial role in cardioprotection.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Hatter Institute for Cardiology Research, Interuniversity Cape Heart Research Group of the Medical Research Council, University of Cape Town Medical School, Observatory, 7925, Cape Town, South Africa. jminners@samiot.uct.ac.za
authors.forename: J
authors.initials: J
authors.lastname: Minners
authors.forename: E J
authors.initials: EJ
authors.lastname: van den Bos
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
authors.forename: H
authors.initials: H
authors.lastname: Schwalb
authors.forename: L H
authors.initials: LH
authors.lastname: Opie
authors.forename: M N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D004140:Dinitrophenols / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis; D006880:Hydroxy Acids / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D020318:Rats, Long-Evans; D014292:Trimetazidine / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D004140:Dinitrophenols; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D014475:Uncoupling Agents; C052853:5-hydroxydecanoic acid; D016572:Cyclosporine; D014292:Trimetazidine