title: The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion.
abstract: 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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: G
authors.initials: G
authors.lastname: Ambrosio
authors.forename: J L
authors.initials: JL
authors.lastname: Zweier
authors.forename: J T
authors.initials: JT
authors.lastname: Flaherty
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003327:Coronary Disease / Q000378:metabolism*; D004734:Energy Metabolism; D005260:Female; D005609:Free Radicals; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D011817:Rabbits
chemical_list: D005609:Free Radicals; D010710:Phosphates; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D010100:Oxygen