Glutathione protects against myocardial ischemia-reperfusion injury by detoxifying peroxynitrite

Peroxynitrite (ONOO-) formation during acute reperfusion of the ischemic he art contributes to the poor recovery of mechanical function. As glutathione (GSH) detoxifies ONOO-, we studied whether it could protect isolated rat h earts subjected to exogenous ONOO- or to ischemia-reperfusion. We showed th at GSH (300 mu M, n=5) abolished the detrimental effect of ONOO- (80 mu M, n=5) on mechanical function of aerobically perfused hearts. Hearts were sub jected to 25 min aerobic perfusion. 20 min global, no-now ischemia and 30 m in reperfusion. GSH (3-300 mu M, n = 7-12) or saline vehicle (control. n = 22) were infused For 10 min prior to ischemia and throughout reperfusion. D uring 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 dit yrosine (a marker of ONOO- formation) in the coronary effluent during reper fusion was significantly reduced in GSH-treated hearts, The concentration o f myocardial cGMP was significantly elevated by GSH during ischemia and ear ly reperfusion. GSH improves the recovery of myocardial mechanical function after ischemia-reperfusion, an effect which may be related to the detoxifi cation of ONOO- by GSH and the stimulation of soluble guanylate cyclase. (C ) 2000 Academic Press.