Oxygen radical toxicity has been implicated in the pathogenesis of
myocardial reperfusion injury. In the present study we sought to document the existence of a precise temporal relationship between the time course of
free radical generation and the time course of alterations of myocardial energy metabolism during early reperfusion. Rabbit hearts perfused within the bore of a 31-Phosphorous NMR spectrometer were subjected to 30 min of total global
ischemia at 37 degrees C. At reflow, 12 control hearts received a bolus of normal perfusate and 12 hearts recombinant human
superoxide dismutase (h-SOD) as a 60,000 IU bolus followed by a 100 IU/ml infusion for 15 min.
Ischemia resulted in similar depletion of tissue
ATP and
phosphocreatine (PCr) in the two groups. During the first minute of reflow, recovery of PCr was similar in both groups. However, PCr recovery arrested in control hearts after 2 min, at 63% of baseline, and averaged 64 +/- 4% after 45 min of reperfusion. In contrast, h-SOD treated hearts recovered 86.7% of baseline PCr content after 2 min, 102% after 10 min of reperfusion (P less than 0.001), and 93 +/- 6.4% at the end of the 45 min of reflow (P less than 0.01). The time course of
free radical formation during reperfusion was assessed by EPR spectroscopy using both the frozen tissue and the spin trapping methodologies. In control hearts, peak generation of
oxygen radicals was reached after 20 s of reflow. h-SOD treatment decreased concentrations of the
oxygen-centered radicals in myocardial tissue and of the radical-adducts in the coronary effluent by approximately 80%. Thus, in reperfused hearts peak
oxygen radical generation is followed by the occurrence of alterations in the recovery of high energy
phosphate metabolism. Both events were largely prevented by administration of h-SOD at reflow. These results provide strong support for a link between
oxygen free radical generation and post-ischemic
reperfusion injury.