title: Role of endothelin, nitric oxide and L-arginine release in ischaemia/reperfusion injury of rat heart.
abstract: OBJECTIVE
  We tested the hypothesis that endothelin-1 (ET-1) aggravates ischaemia/reperfusion injury by stimulating cellular L-arginine depletion, which would result in reduced synthesis of nitric oxide (NO) and withdrawal of cardioprotection.
  
  
  METHODS
  Five groups of rat hearts (n = 5 each) were perfused at 9 ml/min per g for 45 min, subjected to 15 min total global ischaemia and reperfused for 30 min; they received, from 5 min pre-ischaemia to end of reperfusion, either vehicle, L-arginine (1 mmol/l), the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; 200 mumol/l), the inhibitor of NO formation NG-nitro-L-arginine (L-NNA; 200 mumol/l), or the ET receptor antagonist PD 142893 (200 nmol/l). Cardiac function and release of L-arginine, cyclic GMP and lactate dehydrogenase (LDH) into coronary effluent were measured.
  
  
  RESULTS
  Systolic, diastolic, and coronary reperfusion function were consistently improved by L-arginine, SNAP, or PD 142893, but worsened by L-NNA (P < 0.05 in each case). L-arginine release was transiently increased up to 25-fold on reperfusion (vehicle); release was reduced by SNAP (mean: 68%) and entirely prevented by PD 142893. Despite the increased outflow of L-arginine, formation of cyclic GMP was not reduced, but enhanced in reperfusion (11-fold; vehicle), and SNAP further augmented this release, but L-NNA had no significant effect. Release of LDH was decreased by L-arginine, SNAP, and PD 142893 in reperfusion. Finally, release of ET-1 was inhibited by NO in normoxia as well as throughout reperfusion as evident from the stimulatory effect of L-NNA.
  
  
  CONCLUSIONS
  In ischaemia, ET-1 cause cell necrosis and L-arginine outflow without compromising NO synthesis in this model.
authors.affiliation: Institut für Pharmakologie und Toxikologie Karl-Franzens-Universität Graz, Austria. friedrich.brunner@kfunigraz.ac.at
authors.forename: F
authors.initials: F
authors.lastname: Brunner
authors.forename: B
authors.initials: B
authors.lastname: Leonhard
authors.forename: W R
authors.initials: WR
authors.lastname: Kukovetz
authors.forename: B
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D014665:Vasodilator Agents; C076213:PD 142893; D019335:Nitroarginine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D006152:Cyclic GMP