The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion

Abstract

Free radicals such as superoxide (O2−) produced by xanthine oxidase might cause cell death during reperfusion after myocardial ischemia. The effect of the xanthine oxidase inhibitor allopurinol on infarct size in ischemiareperfusion models has been variable, possibly because of differences in treatment duration. Adequate inhibition of xanthine oxidase may require a sufficient pretreatment period to permit conversion of allopurinol to oxypurinol, the actual inhibitor of superoxide production. To test more definitively whether xanthine oxidase-derived free radicals cause cell death during reperfusion, the effect of oxypurinol on infarct size was evaluated in an ischemia-reperfusion model.Open chest dogs underwent 40 min of circumflex coronary artery occlusion followed by reperfusion for 4 days. Twelve dogs were treated with oxypurinol (10 mg/kg body weight intravenously 10 min before occlusion and 10 mg/kg intravenously 10 min before reperfusion) and 11 control dogs received drug vehicle alone (pH 10 normal saline solution). Nine control dogs from a concurrent study also were included. Infarct size was measured histologically and analyzed with respect to its major baseline predictors, including anatomic area at risk and collateral blood flow (measured with radioactive microspheres).Infarct size as a percent of the area at risk averaged 23.8 ± 2.7% (mean ± SEM) in the oxypurinol group (n = 10) and 23.1 ± 4.2% in the control group (n = 17) (p = NS). Collateral blood flow to the inner two thirds of the ischemic wall averaged 0.08 ± 0.01 ml/min per g in the oxypurinol group and 0.09 ± 0.02 ml/min per g in the control group. In control dogs, infarct size was inversely related to collateral flow; oxypurinol did not shift this relation (analysis of covariance F = 0.029, p = NS). Thus, oxypurinol did not limit infarct size. These results suggest that xanthine oxidase-derived free radicals do not cause myocardial cell death during the early reperfusion period after 40 min of ischemia.