© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Role of endothelin, nitric oxide and L-arginine release in ischaemia/reperfusion injury of rat heart
aInstitut für Pharmakologie und Toxikologie Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
bInstitut für Zoologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
* Corresponding author. Tel. +43-316-380-5559; fax: +43-316-380 9890; e-mail: friedrich.brunner@kfunigraz.ac.at
Objectives: 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 µmol/l), the inhibitor of NO formation NG-nitro-L-arginine (L-NNA; 200 µmol/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. Conclusion: In ischaemia, ET-1 causes cell necrosis and L-arginine outflow without compromising NO synthesis in this model.
KEYWORDS Nitric oxide; Nitric oxide donor; Ischaemic cell death; Reperfusion injury; Endothelin; Vascular endothelium; Rat
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