MARKED REDUCTION IN MYOCARDIAL INFARCT SIZE DUE TO PROLONGED INFUSIONOF AN ANTIOXIDANT DURING REPERFUSION

Background There has been controversy about whether early reperfusion of myocardial infarcts causes further necrosis mediated by reactive ox ygen species or other mechanisms. Unequivocal evidence that therapeuti c agents given only during reperfusion can prevent, rather than delay or modify, injury has been sparse. Failure to account for variables, s uch as collateral blood flow, that influence infarct size independentl y and attempts to measure infarct size too early in reperfusion may ha ve limited the sensitivity and specificity of some previous studies. M ethods and Results After 90 minutes of coronary occlusion and 48 hours of reperfusion in a canine model, we examined the effect on infarct s ize of intravenous infusion of N-(2-mercaptopropionyl)-glycine (MPG), a diffusible antioxidant. Infarct size and region at risk were measure d by postmortem dual perfusion with triphenyl tetrazolium chloride and Evans blue dyes, and regional myocardial blood flow was measured with radioactive microspheres. Infusion of MPG 100 mg.kg(-1).h(-1), beginn ing either 15 minutes before the onset of reperfusion or 30 minutes af ter the onset of reperfusion and continued until 4 hours of reperfusio n and followed by an intramuscular dose, reduced infarct size, normali zed for both region at risk and the level of collateral blood flow, by 60% and 45%, respectively. When infusion of MPG was limited to the la st 15 minutes of ischemia and the first hour of reperfusion only, the normalized infarct size was reduced by 26%. Heart rate, blood pressure , and their product did not differ among the four groups studied. The plasma half-time of MPG was <10 minutes. In in vitro experiments MPG w as a scavenger of hydrogen peroxide but not of superoxide radical. Con clusions After 90 minutes of coronary ligation, infusion of the diffus ible hydrogen peroxide scavenger, MPG, for several hours, beginning as late as 30 minutes after the onset of reperfusion, substantially redu ced infarct size measured 48 hours later. In this model, necrosis caus ed by processes during reperfusion may be more extensive than necrosis caused by ischemia alone. Since infusion of this agent for only the f irst hour of reperfusion was considerably less effective, it appears t hat most of the oxidant injury leading to necrosis occurred after the first 60 minutes but within the first 4 hours of reperfusion.