Exogenous intracellular, but not extracellular, iron augments myocardial reperfusion injury.
Although previous studies using iron chelators suggest that iron-catalyzed reactions exacerbate myocardial injury, a direct demonstration of the timing, sites, and mechanisms of iron-mediated damage during reperfusion has been lacking. Catalytic doses of redox-active iron react with exogenously administered oxygen radical-generating systems to exacerbate myocardial injury. In an analogous manner, catalytic doses (5 microM) of excess iron present during early reperfusion should augment oxidative injury, if the redox-active iron is present in the same compartment as both the oxygen radicals generated during reperfusion as well as the critical biochemical targets of oxidative injury. We determined whether catalytic doses of iron given during early reperfusion could exacerbate myocardial injury and whether iron-catalyzed injury required intra- or extracellular iron. Buffer-perfused rabbit hearts underwent 30 min of 37 degrees C global ischemia and 30 min of reperfusion. Iron (5 microM), attached to ligands that either restrict iron to the extracellular space (ADP) or facilitate the entry of iron into myocytes (omadine, tropolone), was infused during the last 3 min of ischemia and the first 4 min of reperfusion. Recovery of developed pressure was decreased (P < 0.05) in omadine-iron and tropolone-iron compared with ADP-iron and noniron hearts treated with ligands alone. Tissue lipid peroxide levels, an index of oxidative injury, were increased (P < 0.05) by omadine-iron and tropolone-iron, but not ADP-iron. The oxidative damage caused by omadine-iron was blocked by pretreatment with dimethylthiourea, a cell-permeable scavenger of the hydroxyl radical.(ABSTRACT TRUNCATED AT 250 WORDS)