Evidence for a reversible oxygen radical-mediated component of reperfusion injury: reduction by recombinant human superoxide dismutase administered at the time of reflow.

Abstract

It has been suggested that the beneficial effects of reperfusing ischemic myocardium might be in part reversed by the occurrence of "reperfusion injury." One possible mechanism could be the generation of oxygen free radicals. Superoxide dismutase enzymtically scavenges superoxide radicals by dismutation to hydrogen peroxide. This study tested the hypothesis that administration of recombinant human superoxide dismutase (h-SOD) at the time of reflow after a period of prolonged global ischemia would result in improved recovery of myocardial metabolism and function by preventing or reducing a potentially harmful component of reperfusion. We also sought to determine whether catalase, an enzymatic scavenger of hydrogen peroxide, was a necessary addition for optimal benefit. Langendorff perfused rabbit hearts were subjected to 30 min of normothermic (37.degree. C) total global ischemia. At the moment of reperfusion, 12 control hearts received a 10 ml bolus of normal perfusate followed by 15 min of reperfusion with normal perfusate (group I), 12 hearts receive 60,000 IU of h-SOD as a bolus followed by a continuous infusion of 100 IU/ml for 15 min (group II), and 12 hearts received 60,000 IU of h-SOD and 60,000 IU of catalase as a bolus followed by 100 IU/ml of both enzymes for 15 min (group III). Myocardial ATP and phosphocreatine (PCr) content and intracellular pH during ischemia and reperfusion were continuously monitored with 31P nuclear magnetic resonance (NMR) spectroscopy. During 30 min of normothermic global ischemia intracellular pH dropped from 7.11-7.18 to 5.58-5.80 in all three groups or hearts. Likewise myocardial PCr content fell rapidly to 7% to 8% and ATP fell more slowly to 29% to 36% of preischemic control content. After 45 min of reperfusion PCr recovered to 65 .+-. 5% of control untreated (group I) hearts compared with 89 .+-. 8% in h-SOD-treated (group II) hearts (p < .01 vs group I) and with 83 .+-. 6% of control in h-SOD/catalase-treated (group III) hearts (p < .05 vs group I). Recovery of isovolumic left ventricular developed pressure was 68 .+-. 5% of control of h-SOD-treated (group II) hearts and 66 .+-. 6% of control in h-SOD/catalase-treated (group III) hearts after 45 min of reflow, compared with 48 .+-. 6% of control in untreated (group I) hearts (p < .005 for groups II and III vs group I). The NMR data confirmed equal depletion of ATP and PCr content in all three groups of hearts. Thus, despite an equally severe ischemic insult, heart receiving h-SOD at the time of reperfusion recovered significantly better PCr content and left ventricular function. Catalase provided no additional benefit. These results clearly demonstrate that reperfusion of ischemic myocardium results in a separate component of myocardial injury, which can be reduced or prevented by administration of the oxygen free radical scavenger, h-SOD, at the time of reperfusion.