Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

Abstract

Glutathione peroxidase is an important enzyme in the degradative cascade of reactive oxygen free radicals. N-Acetylcysteine (NAC) is a low molecular weight compound that has been used clinically to replenish glutathione. To assess the role of the glutathione redox pathway on reperfusion injury, 23 animals underwent 90 minutes of proximal left anterior descending coronary artery occlusion followed by 24 hours of reperfusion with the administration of NAC (n = 11) or saline (n = 12) beginning 30 minutes into occlusion and continuing for 3 hours after reperfusion. Regional ventricular function was measured with contrast ventriculography, and regional myocardial blood flow was determined with microspheres. At 24 hours, the area at risk was defined in vivo with Monastral Blue, and the area of necrosis was defined by incubation in triphenyltetrazolium. Biopsies were taken from the ischemic and nonischemic zones to determine levels of total glutathione, superoxide dismutase and glutathione peroxidase activity, and reactivity to thiobarbituric acid, an index of lipid peroxidation. The rate-pressure product and myocardial blood flow were similar in the two groups throughout the study. No significant differences were noted in infarct size expressed as a percentage of the area at risk (28.6 +/- 5.3% vs. 36.6 +/- 6.0%) and of the total left ventricle (14.4 +/- 3.2% vs. 16.5 +/- 3.1%), and no differences were noted between the two groups on examination of the ischemic subendocardium by light and electron microscopy. Both groups exhibited similar degrees of dyskinesis during occlusion; however, treated animals showed significant improvement in regional radial shortening at 3 hours (3.4 +/- 2.4% vs. -2.4 +/- 2.1%, p less than 0.02) and 24 hours (9.2 +/- 2.2% vs. -2.5 +/- 6.3%, p less than 0.001) after reperfusion. No differences were present in total glutathione, thiobarbituric acid reactivity, or superoxide dismutase and glutathione peroxidase activity in the ischemic zones of the two groups. This study suggests that N-acetylcysteine treatment before reperfusion may reduce myocardial stunning but does not limit myocyte death after reperfusion.