Reperfusion of ischemic myocardium has been postulated to result in a specific
oxygen radical-mediated component of tissue injury. In a previous study we demonstrated improved recovery of ventricular function and metabolism when the
superoxide radical scavenger
superoxide dismutase was administered at the time of postischemic reflow. Studies in vitro, have suggested that
superoxide toxicity might be mediated via the generation of more reactive
hydroxyl radicals in an
iron-catalyzed reaction. The present study was designed to test the hypothesis that
myocardial reperfusion injury might be reduced by administration of the
iron chelator deferoxamine at the time of reflow, most likely by preventing
hydroxyl radical formation. Sixteen isolated Langendorff rabbit hearts, perfused within the bore of a superconducting magnet, were subjected to 30 min of normothermic (37 degrees C) total global
ischemia followed by 45 min of reperfusion. At reflow eight treated hearts received
a 10 ml bolus containing 50 mumol of
deferoxamine followed by an infusion of 11 mumol/min for the first 15 min of reflow. The hearts were then perfused with standard perfusate for an additional 30 min. Eight untreated control hearts received a similar bolus of perfusate followed by 45 min of standard reperfusion. Serial 5 min 31P nuclear magnetic resonance spectra were recorded. Myocardial
phosphocreatine (PCr) content fell to 5% to 7% of control during
ischemia in both groups of hearts.
Deferoxamine-treated hearts recovered 99 +/- 10% of control PCr content, while untreated hearts recovered 60 +/- 16% (p less than .05). Intracellular pH fell to 5.9 during
ischemia in both groups, before showing more rapid and complete recovery in treated hearts (p less than .01). Recovery of developed pressure reached 70 +/- 6% of control in treated hearts compared with 35 +/- 10% in untreated hearts (p less than .05).
Iron content of the perfusate was 7 microM, and by electron paramagnetic resonance spectroscopy was in the form of Fe3+-
EDTA complexes. In the effluent of treated hearts
iron was in the form of Fe3+-
deferoxamine chelates. In summary, administration of the
iron chelator deferoxamine at the time of postischemic reflow results in greater recovery of myocardial function and energy metabolism, which supports the hypothesis that
iron plays an important role in the pathogenesis of
reperfusion injury.