Superimposition of cardioplegic arrest on acute low-cardiac-output states, as may occur after failure of percutaneous transluminal coronary angioplasty requiring emergency surgery, is associated with an increased operative risk. This increased risk is possible attributable to reperfusion, which, after sequential episodes of myocardial ischemia, exacerbates tissue injury mediated by oxygen free radicals. One of the most cytotoxic of these active oxygen species in the hydroxyl radical, which is formed from superoxide anion and hydrogen peroxide through an iron-catalyzed reaction. This study assesses the effects of peroxidase, a hydrogen-peroxide scavenger, and of deferoxamine, an iron chelator, in isolated working rat hearts subjected to 30 minutes of low-flow ischemia (75% reduction in coronary flow) followed by 2 hours of cardioplegic arrest at 15°C and by 30 minutes of normothermic reperfusion. Three groups of hearts (n = 7) were studied. Two groups were pretreated with either peroxidase (10,000 units/l) of deferoxamine (0.03 mM) during the last 15 minutes of the low-flow ischemic period. The third group received no prearrest intervention and served as a control group. In addition to hemodynamic determinations, high-energy phosphate content [adenosine 5'-triphosphate (ATP)] and intracellular pH were monitored serially by 31P nuclear magnetic resonance spectroscopy. The two pretreated groups had better recovery of ATP levels and aortic flow values than did the control group. Overall, deferoxamine pretreatment resulted in the best myocardial protection as evidenced by: 1) the highest postischemic aortic flow values (77% ± 3% of baseline values vs. 67% ± 4% in the peroxidase group and 53% ± 3% in the control group, p < 0.001 vs. controls); 2) the highest total myocardial phosphorus content during arrest (101% ± 5% of baseline values vs. 88% ± 2% in the peroxidase group, p < 0.001; and vs. 89% ± 2% in the control group, p < 0.001) and during reperfusion (99% ± 2% of baseline values vs. 94% ± 2% in the peroxidase group and 88% ± 2% in the control group, p < 0.001 vs. controls); and 3) postischemic ATP levels that were as high as those in the peroxidase groups despite significantly faster heart rates (101% ± 4% of baseline vs. 80% ± 3%, p < 0.001). We conclude that interventions that inhibit hydroxyl radical generation improve cardiac recovery in high-risk situations in which total global ischemia is superimposed on a preceding episode of reduced coronary flow. The excellent results achieved with deferoxamine suggest that reduction of myocardial oxidative injury through iron chelation may be a critical concept for improving cardioplegic protection.