Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion.
BACKGROUND
There has been controversy about whether early reperfusion of myocardial infarcts causes further necrosis mediated by reactive oxygen species or other mechanisms. Unequivocal evidence that therapeutic agents given only during reperfusion can prevent, rather than delay or modify, injury has been sparse. Failure to account for variables, such as collateral blood flow, that influence infarct size independently and attempts to measure infarct size too early in reperfusion may have limited the sensitivity and specificity of some previous studies.


RESULTS
After 90 minutes of coronary occlusion and 48 hours of reperfusion in a canine model, we examined the effect on infarct size of intravenous infusion of N-(2-mercaptopropionyl)-glycine (MPG), a diffusible antioxidant. Infarct size and region at risk were measured by post-mortem 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, beginning either 15 minutes before the onset of reperfusion or 30 minutes after the onset of reperfusion and continued until 4 hours of reperfusion and followed by an intramuscular dose, reduced infarct size, normalized 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 last 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 was a scavenger of hydrogen peroxide but not of superoxide radical.


CONCLUSIONS
After 90 minutes of coronary ligation, infusion of the diffusible hydrogen peroxide scavenger, MPG, for several hours, beginning as late as 30 minutes after the onset of reperfusion, substantially reduced infarct size measured 48 hours later. In this model, necrosis caused by processes during reperfusion may be more extensive than necrosis caused by ischemia alone. Since infusion of this agent for only the first hour of reperfusion was considerably less effective, it appears that most of the oxidant injury leading to necrosis occurred after the first 60 minutes but within the first 4 hours of reperfusion.
Horwitz
L D
LD
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Fennessey
P V
PV
Shikes
R H
RH
Kong
Y
Y
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D007262:Infusions, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D013997:Time Factors; D008625:Tiopronin / Q000008:administration & dosage / Q000627:therapeutic use*
D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D008625:Tiopronin