Iron and the oxygen paradox in ischemic hearts

Reintroduction of oxygen into ischemic tissue causes the formation of reactive oxygen species among which the oxygen radicals. This contributes to the tissue injwy that becomes apparent upon reperfusion. The phenomenon is known as the oxygen paradox. It is known that iron enhances the toxicity of oxygen radicals and that iron is important in the pathology of reperfusion after ischemia. Although this had been shown extensively, it was left unexplained when and how the catalytic iron becomes available. The research described in this thesis addresses the interplay between reduced metabolites of oxygen, reactive oxygen species. and iron in the isolated rat heart. In chapter two it is shov.rn that superoxide dismutase, the enzyme that speeds up the conversion of superoxide to hydrogen peroxide, is not always beneficial in ischerrria/reperfusion experiments showing that this is not the primary toxic species. In chapter three it was shown in hearts from iron loaded rats the iron is localised mainly in the endothelial cells and pericytes. However, no relation was found between functional deterioration and morphological abberations. Chapter four describes a new method to determine the amount of catalytic iron in ischemic hearts. It was shown that ischemia causes a dramatic rise in the amount of catalytic iron and hence predisposes the hearts to oxygen damage. Indeed, in chapter five it was shown that after ischemia rat hearts are more susceptible to hydrogen peroxide through an iron dependent mechanism. This enhanced toxicity could not be induced by anoxic perfusion, in which the hearts were perfused with nitrogen saturated buffer. During anoxia the amount of catalytic iron did not increase suggesting that the accumulation of glycolytic metabolites is essential for ischemic iron release. Subsequently. in chapter six it was shown that interventions that limit the accumulation of reducing equivalents during ischemia, did indeed attenuate the release of iron during ischemia and caused an improved post ischemic recovery. These results of these studies lead to the conclusion that it is the reductive release of iron during ischemia that causes the toxicity of oxygen radicals upon reperfusion. Tne ferrous iron reacts with hydrogen peroxide to form the more toxic ox-ygen radicals that induce tissue injury.