RELEVANCE OF REACTIVE OXYGEN SPECIES FOR REPERFUSION DAMAGE

Enhanced formation of radicals during postischemic reperfusion, foremo st of superoxide (O2-) and hydroxyl (OH) radicals, has been directly a nd indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidan ts, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), mak es it prudent to speak of reactive oxygen metabolites in conjunction w ith cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molec ular 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 exogenou sly applying reactive oxygen species, and (3) the propensity of a grea t variety of antioxidative and radical scavenging measures to afford c ardioprotection during reperfusion. Potential sources of reactive oxyg en metabolites in the reperfused heart are the mitochondrial redox-cha in, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-s ynthase and xanthine oxidase, and formed blood constituents (platelets , monocytes, granulocytes). According to our own results, adenosine, e ndogenously formed in the heart during ischemia, rapidly enhances adhe sion of granulocytes introduced into the coronary system at reperfusio n. Furthermore, small numbers of these cells suffice to induce contrac tile dysfunction in an isolated guinea pig heart model of ischemia-rep erfusion 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-oxida tive measures is largely due to a still rudimentary knowledge of the h omeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-c ourse 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 end ogenous protective systems (e.g., of uric acid in the course of inhibi ting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via en dothelially produced nitric oxide (a scavenger Of O2- and OH) in the i solated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.