title: Treatment of rats with hypolipidemic compound pirinixic acid protects their hearts against ischemic injury: are mitochondrial K(ATP) channels and reactive oxygen species involved?
abstract: Hypolipidemic compound pirinixic acid (WY-14643, WY) is known to exert pleiotropic (other than primary) effects, such as activation of peroxisome proliferator-activated receptors (PPAR-alpha), transcription factors regulating different cardiac functions. Their role in ischemia-reperfusion (I/R) injury and cardioprotection is less clear, although protective effects of PPAR agonists have been documented. This study was designed to explore the effects of WY on the I/R injury in the rat heart and potential mechanisms involved, including mitochondrial K(ATP) channels (mitoK(ATP)) opening and production of reactive oxygen species (ROS). Langendorff-perfused hearts of rats intragastrally treated with WY (3 mg/kg/day) for 5 days and of control animals were subjected to 30-min global ischemia and 2-h reperfusion with or without 15-min perfusion with mitoK(ATP) blocker 5-hydroxydecanoate (5-HD) prior to I/R. Evaluation of the infarct size (IS, TTC staining) served as the main end-point of protection. Lipid peroxidation (a marker of ROS production) was determined by measurement of myocardial concentration of conjugated dienes (CD), whereas protein expression of endothelial NO synthase was analysed by Western blotting. A 2-fold increase in the cardiac protein levels of eNOS after treatment with WY was accompanied by lower post-I/R levels of CD compared with those in the hearts of untreated controls, although WY itself enhanced ROS generation prior to ischemia. IS was reduced by 47 % in the hearts of WY-treated rats (P<0.05), and this effect was reversed by 5-HD. Results suggest that PPAR-alpha activation may confer protection against lethal I/R injury in the rat heart that involves up-regulation of eNOS, mitoK(ATP) opening and reduced oxidative stress during I/R.
authors.affiliation: Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic. usrdravi@savba.sk.
authors.forename: M
authors.initials: M
authors.lastname: Nemčeková
authors.forename: S
authors.initials: S
authors.lastname: Čarnická
authors.forename: M
authors.initials: M
authors.lastname: Ferko
authors.forename: M
authors.initials: M
authors.lastname: Muráriková
authors.forename: V
authors.initials: V
authors.lastname: Ledvényiová
authors.forename: T
authors.initials: T
authors.lastname: Ravingerová
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019610:Cytoprotection; D004195:Disease Models, Animal; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D016277:Ventricular Function, Left
chemical_list: D002316:Cardiotonic Agents; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; C006253:pirinixic acid; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat