Evidence for a pathogenetic role of xanthine oxidase in the "stunned" myocardium

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Abstract
Recent evidence suggest that post-ischemic myocardial dysfunction (or myocardial "stunning") may be mediated by oxygen free radicals, but the mechanism for their production remains unknown. To explore the role of xanthine oxidase as a potential source of free radicals, open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received intravenously either allopurinol (50 mg/kg 48 h, 20 h, and 30 min before occlusion, 10 mg/kg 1 min before REP, and 6.25 mg .cntdot. kg-1 .cntdot. h-1 throughout REP, n = 13) or saline (n = 14). The two groups were similar with respect to occluded bed size (postmortem perfusion) and collateral flow (radioactive microspheres). In controls, the transcardiac difference in plasma uric acid (great cardiac vein - arterial concentration) increased 199 .+-. 70% (means .+-. SE) during ischemia (p < 0.02) and remained elevated for 5 min after REP; no increase was observed in treated dogs. Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. Following REP, however, recovery of contractile function (expressed as percent of preocclusion values) was considerably greater in allopurinol-treated as compared with control dogs: 57 .+-. 14 vs. -22 .+-. 16 (P < 0.01) at 1 h, 70 .+-. 13 vs. -15 .+-. 15 (P < 0.001) at 2 h, 65 .+-. 14 vs. -28 .+-. 13 (P < 0.001) at 3 h, and 68 .+-. 13 vs. -17 .+-. 14 (P < 0.001) at 4 h. These differences could not be ascribed to hemodynamic factors. The results suggest that xanthine oxidase is a source of the oxygen free radicals responsible for myocardial stunning following a brief episode of reversible regional ischemia.