EXOGENOUS INTRACELLULAR, BUT NOT EXTRACELLULAR, IRON AUGMENTS MYOCARDIAL REPERFUSION INJURY

Although previous studies using iron chelators suggest that iron-catal yzed reactions exacerbate myocardial injury, a direct demonstration of the timing, sites, and mechanisms of iron-mediated damage during repe rfusion has been lacking. Catalytic doses of redox-active iron react w ith exogenously administered oxygen radical-generating systems to exac erbate myocardial injury. In an analogous manner, catalytic doses (5 m u M) of excess iron present during early reperfusion should augment ox idative injury, if the redox-active iron is present in the same compar tment as both the oxygen radicals generated during reperfusion as well as the critical biochemical targets of oxidative injury. We determine d whether catalytic doses of iron given during early reperfusion could exacerbate myocardial injury and whether iron-catalyzed injury requir ed intra- or extracellular iron. Buffer-perfused rabbit hearts underwe nt 30 min of 37 degrees C global ischemia and 30 min of reperfusion. I ron (5 mu M), attached to ligands that either restrict iron to the ext racellular 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 de creased (P < 0.05) in omadine-iron and tropolone-iron compared with AD P-iron and noniron hearts treated with ligands alone. Tissue lipid per oxide levels, an index of oxidative injury, were increased (P < 0.05) by omadine-iron and tropolone-iron, but not-ADP-iron. The oxidative da mage caused by omadine-iron was blocked by pretreatment with dimethylt hiourea, a cell-permeable scavenger of the hydroxyl radical. Thus only intracellular iron increased myocardial oxidative injury during early reperfusion, probably mediated by intracellular hydroxyl radical gene ration.