Effects of ischemia and reperfusion on cardiac tolerance to oxidative stress

Abstract

Oxidative stress may affect cardiac function and metabolism. Oxidants are normally inactivated by reacting with reduced glutathione (GSH), with resulting formation and release of oxidized glutathione (GSSG). However, ischemia might affect glutathione metabolism. This might render ischemic hearts less resistant against subsequent oxidant injury during reperfusion, and it might also affect the reliability of GSSG measurements as a means to investigate oxidative stress in reperfused hearts. We compared the metabolic and functional consequences of an oxidant load in control rabbit hearts and in hearts reperfused after 30 min of normothermic total ischemia. In controls, H2O2 infusion (H2O2; 5-30 microM) induced a dose-dependent stimulation of GSSG release and a progressive impairment of cardiac function. At these doses, H2O2 challenge of postischemic hearts resulted in biochemical and functional changes identical to those observed in controls. Release of lactate dehydrogenase (LDH) and of GSH was negligible, similar in both groups. In additional experiments, infusion of H2O2 at a much higher dose (200 microM) elicited a further increase in GSSG release from both groups, although GSSG concentrations were lower in postischemic hearts. The functional effects of the 200 microM H2O2 infusion were similar in both groups, all hearts showing rapid and irreversible deterioration of function. Occurrence of irreversible cell injury was also manifested by a large release of LDH and GSH to a similar extent in both groups. These data demonstrate that cardiac tolerance toward oxidants is largely unaffected by a relatively brief episode of severe ischemia and indicate that GSSG release can be reliably used to investigate oxidative stress in reperfused hearts.

Relationship between oxidative stress, lipid peroxidation, and ultrastructural damage in patients with coronary artery disease undergoing cardioplegic arrest/reperfusion

“…It is only when defense mechanisms are overwhelmed that oxidant attack progresses to injuring cells. In fact, oxidant concentrations capable to elicit cardiac glutathione release larger than what found in this and previous clinical studies, have no detrimental effects, which nonetheless can be induced by up-titration of oxidants [38,39,42].…”

“…However, although cardiac formation and release of glutathione is induced by oxidants [22,38,39], and consistently found during postischemic reperfusion [40,41], this may be simply an indication of exposure to ROS. It is only when defense mechanisms are overwhelmed that oxidant attack progresses to injuring cells.…”

Redox Modulation of Endothelial Nitric Oxide Synthase by Glutaredoxin-1 through Reversible Oxidative Post-Translational Modification

“…It has been asserted that, under normal physiological conditions, cellular GSSG concentrations may not reach a thermodynamically favorable level that can effectively S-glutathionylate protein thiols to redox-modulate protein function (41, 42). Previously, we have identified an efficient mechanism, in which the formation of S-glutathionylated protein thiols of eNOS can go through a labile intermediate protein thiyl radical generated by ROS followed by the reaction with GSH under oxidative stress (32).…”

“…The discovery of eNOS S-glutathionylation by Grx1 provides an additional pathway for redox modulation of eNOS function under oxidative stress that may be more efficient and sensitive than GSSG acting alone. During ischemia/reperfusion injury, the export of GSSG from cells was reported (42, 46). This can lead to an increase in the GSSG/GSH ratio and decrease in the total GSH pool.…”

Protection Against Ischamia-Reperfusion Induced Oxidative Stress by Vitamin E Treatment

“…It has been reported that the isolated rabbit heart, recovering from 30 min of severe ischaemia, retains intact tolerance to H 2 O 2 induced oxidative stress (Ambrosio et al, 1992). We have studied the response of rat heart to oxidative challenge determining the relationship between light emission and homogenate concentration in free radical-induced luminescent reaction.…”