The cardioprotective effect of γ‐glutamylcysteine ethyl ester during coronary reperfusion in canine hearts

Abstract

1 The cardioprotective effect of y-glutamylcysteine ethyl ester was investigated on ischaemia-reperfusioninduced myocardial damage in anaesthetized dogs. 2 Open chest anaesthetized dogs were divided into four groups: 2h occlusion of the left anterior descending coronary artery (LAD); 2 h LAD occlusion followed by h reperfusion; 2 h LAD occlusion followed by h reperfusion with administration of y-glutamylcysteine ethyl ester (lOmgkg1 just before reperfusion); 2 h LAD occlusion followed by 1 h reperfusion with administration of GSH (the reduced form of glutathione, 10mg kg-1 just before reperfusion). 3 After occlusion or reperfusion, heart mitochondria were prepared from the normal area and the occluded or the reperfused area, and mitochondrial function (rate of oxygen consumption in State III, and respiratory control index) was measured polarographically. 4 Mitochondrial GSH and GSSG (the oxidized form of glutathione) concentrations, and activities of glutathione peroxidase and glutathione reductase were measured. 5 Two h of LAD occlusion induced mitochondrial dysfunction with depletion of mitochondrial GSH concentration. One h of reperfusion after 2h LAD occlusion induced significant mitochondrial dysfunction associated with a marked depletion of mitochondrial GSH concentration. 6 y-Glutamylcysteine ethyl ester reduced mitochondrial dysfunction and depletion of mitochondrial GSH concentration after 2 h LAD occlusion and 1 h reperfusion. In contrast, GSH did not prevent depletion of mitochondrial GSH concentration and mitochondrial dysfunction after 2 h LAD occlusion followed by 1 h reperfusion. 7 The activities of glutathione peroxidase and glutathione reductase did not change significantly in each group.8 One h of reperfusion after 2 h occlusion of LAD induced ventricular arrhythmias. y-Glutamylcysteine ethyl ester markedly reduced the development of reperfusion arrhythmias, whilst GSH showed no protective effect. 9 y-Glutamylcysteine ethyl ester maintained mitochondrial GSH concentration, prevented reperfusion myocardial damage, and reduced reperfusion arrhythmias.

Elevated glutathione as a therapeutic strategy in Alzheimer's disease

“…In order to increase the efficacy of g-glutamylcysteine transport across the membrane, several investigators have administered g-glutamylcysteine ethyl ester (GCEE) in order to increase GSH levels in various cell types and systems, including ischemiareperfusion in liver [Kobayashi et al, 1992;Ozaki et al, 1994] and in heart [Hoshida et al, 1994;Nishinaka et al, 1991], carbon tetrachloride hepatic injury [Nishida et al, 1998], and selenium-deficient heart [Okamoto et al, 1999]. In hepatocytes, GCEE was found to be transported into liver cells more readily than GSH and converted to GSH [Nishida et al, 1996].…”

Novel Inhibitory Effects of γ-Glutamylcysteine Ethyl Ester against Human Immunodeficiency Virus Type 1 Production and Propagation

“…Here, we report on a unique GSH prodrug, ␥-glutamylcysteine ethyl ester (␥-GCE; TEI-2306) (31), which is shown to have novel effects against HIV-1. ␥-GCE possesses a long plasma half-life (more than fivefold longer than that of GSH) and high membrane permeability (more than five times higher than that of GSH) and has been reported to be effective against heart and liver reperfusion injury (13,17,(20)(21)(22), asthma (15), and cataracts (23). In the present study, this compound is shown to possess a unique anti-HIV-1 activity in both chronically and acutely infected cells, and even for free viruses, as opposed to inhibiting oxidative stress-induced increases of HIV-1 transcription.…”

Impaired glutathione biosynthesis in the ischemic‐reperfused rabbit myocardium

“…Administration of GSH precursors without inhibitory effects on G-GCS, such as y-glutamylcysteine [17], could so be considered as cardioprotective agents in the clinical setting. Notably, the beneficial effect of y-glutamylcysteine ethyl ester, as a result of cell GSH preservation, has been proved in the canine myocardium subjected to severe ischemia and reperfusion [23].…”