Myocardial glutathione depletion impairs recovery after short periods of ischemia.

Abstract

Isolated, isovolumic rat hearts, perfused by Krebs-Henseleit buffer at constant coronary flow rate, were used to explore the hypothesis that endogenous cardiac glutathione provides protection against myocardial dysfunction associated with short periods of ischemia. Experimental animals were depleted of cardiac glutathione to 35% of control levels by intraperitoneal injections of diethylmaleate (DEM). Left ventricular pressure, coronary perfusion pressure, and glutathione levels were measured in control and experimental hearts after 60 minutes of oxygenated perfusion and after 20 minutes of global, no-flow ischemia and 30 minutes of reperfusion. With each protocol, both control and glutathione-depleted hearts received either standard buffer or one supplemented with 2 mM glutathione. Recovery of systolic function after ischemia-reperfusion was impaired in DEM-treated hearts compared with controls. In addition, the rise in perfusion pressure and chamber stiffness was also greater in DEM-treated hearts compared with controls. Recovery in glutathione-depleted hearts was improved when the reperfusate was supplemented with glutathione. In addition, the supplemented reperfusate prevented the decrease in compliance and the increase in coronary perfusion pressure in the glutathione-depleted hearts. Ischemia-reperfusion alone were not associated with a significant alteration in myocardial glutathione levels. Prewashout myocardial levels of glutathione were elevated after reperfusion with glutathione-supplemented bulfer but fell to baseline levels after a short washout period. These studies demonstrate that endogenous glutathione is important in protection of myocardium from injury after ischemia-reperfusion, presumably by modifying levels of active oxygen intermediates. The smaller changes in left ventricular pressure and coronary resistance after administration of GSH probably reflects an extracellular mechanism because benefit is seen soon after reperfusion. (Circulation 1989;80:1449-1457 D uring oxidative metabolism, cells produce potentially toxic oxygen radicals for which both specific and nonspecific scavenging mechanisms are present. Recently, it has been suggested that hypoxia or ischemia, followed by reoxygenation or reperfusion, increases production of oxygen radical species.1-5Administration of exogenous quenchers of free radicals, such as superoxide dismutase (SOD), catalase or both, improve cardiac function and limit infarct size when administered after experimental global ischemia.6,7From the Cardiology Section,

Beneficial effects of N‐acetylcysteine and cysteine in stunned myocardium in perfused rat heart

“…Winniford et al (1986) have shown that NAC could potentiate the coronary vasodilator effect of nitroglycerin in man, as shown by an increase in coronary sinus blood flow. Blaustein et al (1989) demonstrated that GSH administration could prevent an increase in coronary vascular resistance during 30min of reperfusion after 20 min of ischaemia in isolated rat heart, suggesting that GSH may be particularly important in protecting the coronary vasculature. Other studies also show that some of the microvascular damage may be caused by free radicals because this damage is decreased by free radical scavengers Zweier et al, 1988).…”

Time Course of Erythrocyte Antioxidant Activity in Patients Treated by Thrombolysis for Acute Myocardial Infarction.

“…19,27) At the same time of evolving AMI, several groups reported an increased concentration of plasma malondialdehyde 4,5,27) as well as decreased glutathione levels. 8,27) Decreased catalase activity and decreased levels of vitamin E have also been described. 11,12) Taken together, these results confirm that the oxidative/antioxidative balance is disturbed early, during the ischaemic phase of AMI.…”

“…However, the mechanisms underlying oxidative stress in patients treated by thrombolysis for acute myocardial infarction (AMI) are still not clearly understood. It is generally thought that with the reperfusion of previously ischaemic myocardium there is a concurrent rapid release of oxygen derived free radicals [1][2][3] leading to peroxidation of lipids [4][5][6][7] and depletion of both endogenous antioxidants [8][9][10] and antioxidant vitamins. 7,11,12) These factors contribute to the development of reperfusion injury characterized by temporary impairment of systolic function 1,10) and arrhythmias.…”

Effect of ethanol extract ofEmbelia ribesfruits on cardiac changes in rats subjected to ischemic reperfusion injury

“…Blaustein et al (1989) also demonstrated that GSH is important in protecting the myocardium against OFR injury and that a reduction in cellular GSH content would impair recovery after short periods of ischemia. In the present study, myocardial endogenous antioxidant (GSH, GPx, GR and GST) levels were significantly decreased in the IR group as compared to the sham operated group (group I).…”