MYOCARDIAL PROTECTION Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs

During the acute phase of myocardial ischemia, adenine nucleotides are degraded to nucleosides and bases, especially inosine and hypoxanthine. Simultaneously, xanthine dehydrogenase is converted to xanthine oxidase, an enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid, producing a superoxide anion for each molecule of hypoxanthine or xanthine oxidized. To determine if free radicals via this enzymatic source contribute to cell death in myocardial ischemia, we determined whether allopurinol, an inhibitor of xanthine oxidase, could limit infarct size in a reperfusion preparation of myocardial infarction. The circumflex coronary artery of each of 34 dogs was occluded for 40 min, followed by reperfusion for 4 days. Infarct size then was measured by histologic methods and was related to major baseline predictors of infarct size, including anatomic area at risk and collateral blood flow. Infarct size was larger (NS) in the allopurinol (n = 8) than in the control (n = 1 1) group, a trend that was related to slightly higher (NS) collateral blood flow in the control group. We conclude that allopurinol has no beneficial effect in this preparation of experimental myocardial infarction. The results oppose the hypothesis that free radicals, produced via the xanthine oxidase reaction, are an important contributing factor in myocardial ischemic cell death. Circulation 71, No. 5, 1069-1075, 1985. FR1EE RADICALS, including the superoxide anion (02-) and the hydroxyl radical (OH), have been implicated as causal or contributing factors in a variety of types of cell injury, including myocardial ischemia. `Several metabolic pathways may lead to production of free radicals during ischemia,5'6 including the xanthine oxidase reaction in which hypoxanthine is oxidized to xanthine or xanthine is oxidized to uric acid.' '° The xanthine oxidase reaction is of particular interest because large quantities of hypoxanthine, and its precursor inosine, accumulate rapidly in severely ischemic myocardium as a consequence of the degradation of the purine nucleotides."' 12 Especially when reperfusion is established, the xanthine oxidase reaction, fueled by an initially large substrate supply plus abundant oxygen resulting from reactive hyperemia, might produce an excessive load of superoxide anion. The latter might cause death of myocytes that would otherwise have survived the temporary period of ischemia. From the Department of Pathology, Duke University Medical Center, Durham. Supported by NIH grants HL23138 and HL27416. Address for correspondence: Dr. Keith A. Reimer, Department of Pathology, Duke University Medical Center, Durham, NC 27710. Received Jan. 30, 1985; accepted Feb. 14, 1985. Vol. 71, No. 5, May 1985 If this hypothesis is valid, inhibition of the xanthine oxidase reaction should prevent some or all of the cell death, and thereby limit infarct size in a temporary occlusion/reperfusion setting. Accordingly, the purpose of the present study was to test whether allopurinol, a xanthine oxidase inhibitor, alters myocardial infarct size in a coronary occlusion/reperfusion preparation of ischemic injury.