Therapy to Reduce Free Radicals During

It has been postulated that oxygen-centered free radicals are produced in significant quantities upon reperfusion of ischemic myocardium and could cause the death of myocytes that are still reversibly injured at the end of ischemia ("reperfusion injury"). However, we have shown previously that anti-free radical therapies including superoxide dismutase (SOD) and inhibitors of xanthine oxidase did not limit infarct size after 40 minutes of ischemia and 4 days of reperfusion in dogs. To test whether 40 minutes of ischemia is too brief a period to produce the prerequisite conditions for free radical-mediated necrosis upon reperfusion, we studied infarcts produced by 90 minutes of ischemia followed by reperfusion. Dogs in an SOD-catalase group received a 60-minute infusion of SOD (i5,000 units/kg) and catalase (55,000 units/kg) beginning 25 minutes before and ending 35 minutes after reperfusion. A second group of dogs received a single injection of the xanthine oxidase inhibitor oxypurinol (20 mg/kg) 25 minutes before reperfusion. Infarct size was assessed histologically relative to the size of the area at risk and to collateral blood flow to the ischemic region. Infarct size as a percentage of the area at risk was similar in the control group (40.7 ± 5.5%, n = 11), the SOD -catalase group (38.0 ± 6.4%; n = 8), and the oxypurinol-treated group (41.4 ± 6.1%; n = 7) [p= not significant (NS) by analysis of variance]. In controls, there was an inverse relation between infarct size and collateral blood flow; neither of the treatments altered this relation (p= NS by analysis of covariance). Thus, neither SOD catalase nor oxypurinol limited infarct size. These results suggest that free radicals, produced by xanthine oxidase and/or accessible to the infused SOD and catalase in the early phase of reperfusion, do not cause substantial myocyte death in this model. From this study and our previous studies, we conclude that differences in the duration of ischemia before reperfusion do not explain the variable results among published studies of therapy directed against free radical production. (Circulation 1988;78:473-480)