Glutathione protects against myocardial ischemia-reperfusion injury by detoxifying peroxynitrite.
Peroxynitrite (ONOO(-)) formation during acute reperfusion of the ischemic heart contributes to the poor recovery of mechanical function. As glutathione (GSH) detoxifies ONOO(-), we studied whether it could protect isolated rat hearts subjected to exogenous ONOO(-)or to ischemia-reperfusion. We showed that GSH (300 microm, n=5) abolished the detrimental effect of ONOO(-)(80 microm, n=5) on mechanical function of aerobically perfused hearts. Hearts were subjected to 25 min aerobic perfusion, 20 min global, no-flow ischemia and 30 min reperfusion. GSH (3-300 microm, n=7-12) or saline vehicle (control, n=22) were infused for 10 min prior to ischemia and throughout reperfusion. During reperfusion, GSH caused a concentration-dependent improvement in the recovery of mechanical function, which was not associated with significant changes in the intracellular concentration of GSH. The concentration of dityrosine (a marker of ONOO(-) formation) in the coronary effluent during reperfusion was significantly reduced in GSH-treated hearts. The concentration of myocardial cGMP was significantly elevated by GSH during ischemia and early reperfusion. GSH improves the recovery of myocardial mechanical function after ischemia-reperfusion, an effect which may be related to the detoxification of ONOO(-)by GSH and the stimulation of soluble guanylate cyclase.
Cheung
P Y
PY
Department of Pediatrics, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
Wang
W
W
Schulz
R
R
D000818:Animals; D005978:Glutathione / Q000008:administration & dosage*; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009566:Nitrates / Q000008:administration & dosage; D016877:Oxidants / Q000008:administration & dosage; D010084:Oxidation-Reduction; D051381:Rats
D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D005978:Glutathione