[Possible significance of free oxygen radicals for reperfusion injury]

Enhanced formation of radicals during post-ischemic reperfusion, foremost of superoxide (O2-) and hydroxyl (OH) radicals, has been directly and indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidants, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), makes it prudent to speak of reactive oxygen metabolites in conjunction with cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molecular species includes (1) the increased formation of lipid peroxides, (2) the ability to mimic all facets of reperfusion injury (arrhythmias, contractile and vascular dysfunction, infarct extension) by exogenously applying reactive oxygen species, and (3) the propensity of a great variety of antioxidative and radical scavenging measures to afford cardioprotection during reperfusion. Potential sources of reactive oxygen metabolites in the reperfused heart are the mitochondrial redox-chain, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-synthase and xanthine oxidase, and formed blood constituents (platelets, monocytes, granulocytes). According to our own results, adenosine, endogenously formed in the heart during ischemia, rapidly enhances adhesion of granulocytes introduced into the coronary system at reperfusion. Furthermore, small numbers of these cells suffice to induce contractile dysfunction in an isolated guinea pig heart model of ischemia-reperfusion injury, the major mediator of damage being HOCl. The striking disparity between the enormous volume of experimental data supporting involvement of reactive oxygen metabolites in reperfusion damage and the virtual lack of clinical-therapeutic regimens employing anti-oxidative measures is largely due to a still rudimentary knowledge of the homeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-course and extent of oxidative stress seems to be a major problem. Also, confounding issues such as compartmentation of radical formation as opposed to radical scavenging and the unwitting down-regulation of endogenous protective systems (e.g., of uric acid in the course of inhibiting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via endothelially produced nitric oxide (a scavenger of O2- and OH) in the isolated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.