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 ischemia-reperfusion 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs.

“…First, it is possible that in the presence of a treatment, tetrazolium used early after reperfusion may artifactually stain tissue that is irreversibly injured; this artifact would not be observed when tetrazolium is used after longer periods of reperfusion21,23,25,26 or when infarct size is assessed histologically. 20,22,24 Another possibility is that treatments only delay free radical-induced cell death and that the initially salvaged tissue undergoes necrosis later in the reperfusion phase ("delayed reperfusion injury"). Such a mechanism could occur if free radical production continued after drug levels decreased below their therapeutic levels.…”

Xanthine oxidase inhibition does not limit canine infarct size.

“…The continuation of iloprost therapy until 48 hours after reperfusion did limit the extent of injury assessed 72 hours after reperfusion.33 Thus, it is not surprising that administration of oxypurinol before reperfusion failed to limit the ultimate extent of myocardial injury in dogs subjected to 40 or 90 minutes of coronary artery occlusion followed by reperfusion for 1 or 4 days. [34][35][36] Histochemical reagents such as triphenyltetrazolium chloride and nitro blue tetrazolium impart pigmentation to myocardium that retains the activities of dehydrogenase enzymes and their coenzymes,37 which may not be synonymous with cell viability. Nevertheless, the calculation of the extent of myocardial infarction using triphenyltetrazolium chloride or nitro blue tetrazolium correlates with the assessment of infarct size by electron microscopy,37 histopathology,38,39 the depletion of creatine kinase activity,40 the uptake of infarct-avid radionuclides,41,42 or antimyosin antibodies.43 According to Kloner et al,44 electron microscopic analysis of myocardium confirmed that triphenyltetrazolium chloride "... can reliably identify those areas of myocardium that demonstrate severe ultrastructural damage during the early phases of myocardial infarction, prior to the development of frank necrosis on histologic examination."…”

Intracoronary infusion of superoxide dismutase and reperfusion injury in the pig heart

“…Indeed, when reperfusion is performed rapidly, the protective capability of the scavenger agent may be overwhelmed by the very rapid generation of free radicals (30). Many studies that have shown protective effects have used a slow reperfusion procedure (21,28,49,50), whereas many of the negative studies used a rapid reperfusion protocol (10,13,24,26,34,39,40,41,48). The present study cannot definitively answer the question of whether slow reperfusion is desirable or not.…”

“…supero• dismutase and catalase, and of various agents interfering with their metabolic sources, such as allopurinol to block the xanthine o• pathway, have been evaluated. The protective effects observed in some studies with various animal species (1, 2,4,20,21,32,33,37,50,51) could not, however, bc rcproduced in others (10,13,24,26,34,39,40,41,48). Considering these discrepancies, the usefulness of the therapeutic approach is questionable and, consequently, so is the role played by oxygen radicals in the etiology of reperfusion damage (9).…”