Reduction of infarct size by cell-permeable oxygen metabolite scavengers.
The timely restoration of blood flow to severely ischemic myocardium limits myocardial infarct size. However, experimental studies demonstrate that the myocardial salvage achieved is suboptimal because of additional injury that occurs during reperfusion, due in part to the generation of reactive oxygen metabolites. Initially, superoxide (O2-) was considered to be the central mediator of reperfusion injury. While there are several potential pathways of O2- generation in reperfused myocardium, O2- is poorly reactive toward tissue biomolecules. However, O2-, in the presence of redox-active metals such as iron, generates .OH or hydroxyl-like species that are highly reactive with cell constituents. Thus, while O2- may initiate reaction sequences leading to myocardial injury, it may not be the actual injurious agent. In vitro studies suggest that oxygen metabolite injury occurs at intracellular sites and involves iron-catalyzed processes. Consistent with this mechanism, extracellular oxygen metabolite scavengers have not convincingly reduced infarct size. However, treatment around the time of reperfusion, after ischemia is well established, with cell-permeable scavengers of .OH reduce infarct size. Results with these cell-permeable agents suggest that in the intact animal during regional ischemia and reperfusion, oxygen metabolite injury also occurs at intracellular sites. Cell-permeable scavenger agents are a promising class of drugs for potential clinical use, though further experimental and toxicologic studies are required.
Lesnefsky
E J
EJ
Division of Cardiology, Case Western Reserve University, Cleveland, OH.
D000818:Animals; D002463:Cell Membrane Permeability; D016166:Free Radical Scavengers; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D010100:Oxygen / Q000378:metabolism*
D016166:Free Radical Scavengers; D006878:Hydroxides; D017665:Hydroxyl Radical; D010100:Oxygen