Circulation, Vol 76, 906-915, Copyright © 1987 by American Heart Association
G Ambrosio, JL Zweier, WE Jacobus, ML Weisfeldt and JT Flaherty
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.
ARTICLES
Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
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