title: Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1.
abstract: BACKGROUND
  Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1).
  
  
  METHODS
  Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-alpha agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET-1 mRNA expression were determined.
  
  
  RESULTS
  There were no haemodynamic differences between the groups during the experiment. The IS was 78 +/- 3% of the area at risk in the DMSO group and 77 +/- 2% in the NaCl group (P = NS). WY reduced IS to 56 +/- 3% (P < 0.001 vs. DMSO group). When WY was administered in combination with L-NNA the cardioprotective effect was abolished (IS 73 +/- 3%, P < 0.01 vs. WY 14643). L-NNA did not affect IS per se (78 +/- 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P < 0.05). ET-1 mRNA levels were lower in the ischaemic myocardium following WY administration.
  
  
  CONCLUSIONS
  The results suggest that the PPAR-alpha activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET-1.
authors.affiliation: Department of Cardiology, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. Aliaksandr.Bulhak@ki.se
authors.forename: A A
authors.initials: AA
authors.lastname: Bulhak
authors.forename: P-O
authors.initials: PO
authors.lastname: Sjöquist
authors.forename: C-B
authors.initials: CB
authors.lastname: Xu
authors.forename: L
authors.initials: L
authors.lastname: Edvinsson
authors.forename: J
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D015151:Immunoblotting; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D019335:Nitroarginine; D009569:Nitric Oxide; C006253:pirinixic acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat