Superoxide Dismutase Decreases Reperfusion Arrhythmias and Preserves Myocardial Function During Thrombolysis with Tissue Plasminogen Activator

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Abstract
Release of superoxide radicals during the early phase of coronary reperfusion may result in degradation of endothelium-derived relaxing factor (EDRF), extension of myocardial injury, precipitation of arrhythmias, and stimulation of platelet aggregation. These factors may relate to the occurrence of ventricular fibrillation during reperfusion and coronary reocclusion following initial thrombolysis. This study was designed to examine the effects of concomitant administration of superoxide radical scavenger superoxide dismutase (SOD) with tissue plasminogen activator (tPA) compared to tPA alone (without SOD) in acute coronary thrombosis in anesthetized dogs. Dogs with a stable electrically induced coronary thrombus were randomly given intravenously tPA (0.75 mg/kg) alone or SOD bolus (2 mg/kg) followed by SOD (4 mg/kg) + tPA (0.75 mg/kg) over 20 min. tPA alone restored coronary blood flow in six of nine dogs (reperfusion rate of 67%) with time to reflow of 18.5 ± 6.7 (mean ± SD) min. Coronary reocclusion occurred spontaneously in four of six dogs with initial reperfusion (reocclusion rate of 67%). In contrast, SOD + tPA restored coronary blood flow in 9 of 12 dogs (reperfusion rate of 75%, not significant vs. tPA alone) with time to reflow of 11.3 ± 4.8 min and coronary reocclusion occurred in only 3 of 9 dogs with reperfusion (reocclusion rate of 33%, not significant vs. tPA alone). Reperfusion arrhythmias were more frequent in dogs who received tPA alone compared to those who received SOD in addition to tPA (mean Holter-monitored PVC count of 730 vs. 12 beats/h, p < 0.01). The amount of lidocaine administered to control arrhythmias was also more when tPA was given alone (mean dose of 138 vs. 10 mg, p < 0.01). Regional myocardial segmental function in the reperfused myocardium was improved by SOD plus tPA (shortening fraction from −8.4 to −3.6%, p < 0.02), but not by tPA alone (from −10.7 to −11.9%, not significant). SOD also significantly (p < 0.01) enhanced the platelet aggregation inhibitory effects of tPA in canine whole blood. In other experiments, we documented attenuation of coronary arterial ring relaxation in response to acetylcholine in dogs treated with saline during reperfusion, indicating loss of EDRF. In dogs treated with SOD prior to coronary reperfusion, coronary ring relaxation response to acetylcholine was preserved. This study shows that concomitant administration of SOD with tPA improves the quality of reperfusion with tPA in canine coronary thrombosis in terms of significant reduction in reperfusion arrhythmias and relative preservation of regional myocardial function. The beneficial effects of SOD are probably related to the inhibition of platelet aggregation and preservation of EDRF release during reperfusion.