Glutathione deficiency intensifies ischaemia‐reperfusion induced cardiac dysfunction and oxidative stress

Abstract

The efficacy of glutathione (GSH) in protecting ischaemia-reperfusion (I-R) induced cardiac dysfunction and myocardial oxidative stress was studied in open-chest, stunned rat heart model. Female Sprague-Dawley rats were randomly divided into three experimental groups: (1) GSH-depletion, by injection of buthionine sulphoxamine (BSO, 4 mmol kg(-1), i.p.) 24 h prior to I-R, (2) BSO injection (4 mmol kg(-1), i.p.) in conjunction with acivicin (AT125, 0.05 mmol kg(-1), i.v.) infusion 1 h prior to I-R, and (3) control (C), receiving saline treatment. Each group was further divided into I-R, with surgical occlusion of the main left coronary artery (LCA) for 30 min followed by 20 min reperfusion, and sham. Myocardial GSH content and GSH : glutathione disulphide (GSSG) ratio were decreased by approximately 50% (P < 0.01) in both BSO and BSO + AT125 vs. C. Ischaemia-reperfusion suppressed GSH in both left and right ventricles of C (P < 0.01) and left ventricles of BSO and BSO + AT125 (P < 0.05). Contractility (+dP/dt and -dP/dt) in C heart decreased 55% (P < 0.01) after I and recovered 90% after I-R, whereas +/-dP/dt in BSO decreased 57% (P < 0.01) with ischaemia and recovered 76 and 84% (P < 0.05), respectively, after I-R. For BSO + AT125, +/-dP/dt were 64 and 76% (P < 0.01) lower after ischaemia, and recovered only 67 and 61% (P < 0.01) after I-R. Left ventricular systolic pressure in C, BSO and BSO + AT125 reached 95 (P > 0.05) 87 and 82% (P < 0.05) of their respective sham values after I-R. Rate-pressure double product was 11% (P > 0.05) and 25% (P < 0.05) lower in BSO and BSO + AT125, compared with Saline, respectively. BSO and BSO + AT125 rats demonstrated significantly lower liver GSH and heart Mn superoxide dismutase activity than C rats after I-R. These data indicate that GSH depletion by inhibition of its synthesis and transport can exacerbate cardiac dysfunction inflicted by in vivo I-R. Part of the aetiology may involve impaired myocardial antioxidant defenses and whole-body GSH homeostasis.

Increased Myocardial Dysfunction After Ischemia-Reperfusion in Mice Lacking Glucose-6-Phosphate Dehydrogenase

“…Impaired diastolic and contractile function in G6PD def hearts is similar to the cardiac dysfunction that has previously been shown to occur during ischemia-reperfusion with depletion of cellular glutathione [7][8][9] or with inhibition of glutathione cycling. 32,33 This suggests that G6PD mediates susceptibility to ischemia-reperfusion injury through maintenance of cellular glutathione and protection against oxidative stress.…”

“…5,6 GSH allows for the conversion of deleterious hydrogen peroxide and lipid peroxides to water and alcohols, respectively. 6 Depletion of cardiac GSH exacerbates myocardial ischemia-reperfusion injury, [7][8][9] whereas exogenous supplementation with GSH protects against such injury. 7,10,11 Generation of GSH from its oxidized form, GSSG, and subsequent maintenance of intracellular GSH pools require reducing equivalents in the form of the pyridine nucleotide NADPH.…”

Acute and severe hypobaric hypoxia-induced muscle oxidative stress in mice: the role of glutathione against oxidative damage

“…Besides acting as an electron donor to neutralize hydrogen peroxide (H 2 O 2 ) and lipoperoxide, GSH also scavenges oxygen-and nitrogenbased free radicals (Ji 1999). Based on these antioxidant properties, the effect of GSH has been extensively studied in many experimental models that induce tissue dysfunction by oxidative damage (Ji et al 1994;Leichtweis and Ji 2001), namely acute exercise, ischemiareperfusion and drug administration. With these experimental models, several authors have shown that the depletion of intrinsic GSH exacerbates tissue damage inflicted by many stimuli (Sen et al 1993;Sen et al 1994;Leeuwenburgh and Ji 1995).…”

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

“…Although thrombolytic therapy and percutaneous coronary interventions reduce mortality from acute myocardial infarction, additional therapeutic strategies are needed, given that reperfusion of the ischemic myocardium generates oxygen free radicals 1,2 and that impaired myocardial antioxidant defense capacity leads to tissue injury. 3 Several clinical trials, the Randomized Aldactone Evaluation Study 4 and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, 5 showed decreased mortality with the use of mineralocorticoid receptor antagonists in addition to standard therapy, evidence for a role of mineralocorticoid receptor (MR) activation in myocardial infarction and heart failure. In the Eplerenone PostAcute Myocardial Infarction Heart Failure Efficacy and Survival Study, 32% of the patients were diabetic, and patients randomized early to treatment derived more benefit than those randomized later.…”