Deferoxamine prevents lipid peroxidation and attenuates reoxygenation injury in postischemic skeletal muscle.
In the presence of the transition metal iron, superoxide anion and H2O2 generated on reperfusion of postichemic tissue combine to form hydroxyl radical, which readily attacks membrane-associated polyunsaturated fatty acids in a free radical process, resulting in lipid peroxidation. To evaluate whether iron chelation with deferoxamine interrupts this process in postischemic skeletal muscle, high-grade partial hindlimb ischemia was created in Sprague-Dawley rats by clamping the infrarenal aorta for 90 min, after which period the clamp was removed and flow was reestablished for 60 min. Lipid peroxidation in skeletal muscle was assessed by determination of tissue thiobarbituric acid-reactive substances (TBARS); membrane dysfunction was assessed by measurement of resting membrane potential (Em). Ischemia was accompanied by an increase in muscle TBARS and depolarization of resting Em. On reperfusion, muscle TBARS continued to increase, whereas resting Em remained depolarized. Pretreatment with deferoxamine prevented lipid peroxidation during ischemia but had no effect on resting Em. On reperfusion in the deferoxamine-treated animals, there was still no increase in muscle TBARS, and partial repolarization of resting Em was noted. It is concluded that 1) high-grade partial ischemia in skeletal muscle is accompanied by iron-dependent lipid peroxidation via a mechanism that persists and accelerates on reoxygenation, 2) lipid peroxidation impacts on functional membrane integrity during the reperfusion phase only, and 3) membrane injury accompanying ischemia and reperfusion may occur through fundamentally different mechanisms, of which only the latter is iron dependent.
Fantini
G A
GA
Department of Surgery, New York Hospital, New York 10021.
Yoshioka
T
T
D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology*; D004594:Electrophysiology; D006614:Hindlimb; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D009132:Muscles / Q000098:blood supply* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D008054:Lipid Peroxides; D017392:Thiobarbituric Acid Reactive Substances; D003676:Deferoxamine