Xanthine oxidase: a critical mediator of myocardial injury during ischemia and reperfusion?
Myocardial ischemia initiates a series of cellular reactions which unless checked will culminate in cell death and tissue necrosis. Although reperfusion provides a means of preventing cell death it is not without hazard. In cases of mild ischemia, where tissue injury is in its reversible phase, reperfusion may precipitate potentially lethal ventricular arrhythmias and in cases of severe injury it may actually accelerate the process of cell death leading to hemorrhage and other forms of severe injury. The identity of mediators of cellular injury, and particularly the critical transition from reversible to irreversible injury, remains controversial. Whereas for a number of years ATP depletion, calcium overload and catecholamines have been considered as key factors in tissue injury, attention has recently been directed towards oxygen-derived free radicals (e.g. superoxide and the hydroxyl radical). In this article we discuss sources of free radicals in the mammalian heart (xanthine oxidase, mitochondria, leucocytes, and catecholamines) and present arguments based on quantitative and temporal considerations that the xanthine oxidase-mediated degradation of hypoxanthine is the most important source of free radicals and as such is the most appropriate target for therapeutic intervention. To support our arguments we present data from two species, the dog and the rat, in which we have shown how allopurinol, the specific inhibitor of xanthine oxidase, can afford a reduction of infarct size in the dog and can dramatically reduce the incidence of potentially lethal reperfusion-induced arrhythmias in the rat. Arising from these and other studies is the proposition that anti-free radical interventions (particularly those directed towards xanthine oxidase inhibition) may provide an important new therapeutic principle in the management of ischemia and reperfusion.
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002395:Catecholamines / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D005609:Free Radicals; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D008929:Mitochondria, Heart / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D014969:Xanthine Oxidase / Q000502:physiology*
D002395:Catecholamines; D005609:Free Radicals; D000493:Allopurinol; D014969:Xanthine Oxidase; D010100:Oxygen