DEFEROXAMINE PREVENTS LIPID-PEROXIDATION AND ATTENUATES REOXYGENATIONINJURY IN POSTISCHEMIC SKELETAL-MUSCLE

In the presence of the transition metal iron, superoxide anion and H2O 2 generated on reperfusion of postichemic tissue combine to form hydro xyl radical, which readily attacks membrane-associated polyunsaturated fatty acids in a free radical process, resulting in lipid peroxidatio n. To evaluate whether iron chelation with deferoxamine interrupts thi s process in postischemic skeletal muscle, high-grade partial hindlimb ischemia was created in Sprague-Dawley rats by clamping the infrarena l aorta for 90 min, after which period the clamp was removed and flow was reestablished for 60 min. Lipid peroxidation in skeletal muscle wa s assessed by determination of tissue thiobarbituric acid-reactive sub stances (TBARS); membrane dysfunction was assessed by measurement of r esting membrane potential (E(m)). Ischemia was accompanied by an incre ase in muscle TBARS and depolarization of resting E(m). On reperfusion , muscle TBARS continued to increase, whereas resting E(m) remained de polarized. Pretreatment with deferoxamine prevented lipid peroxidaton during ischemia but had no effect on resting E(m). On reperfusion in t he deferoxamine-treated animals, there was still no increase in muscle TBARS, and partial repolarization of resting E(m) was noted. It is co ncluded that 1) high-grade partial ischemia in skeletal muscle is acco mpanied by iron-dependent lipid peroxidation via a mechanism that pers ists and accelerates on reoxygenation, 2) lipid peroxidation impacts o n functional membrane integrity during the reperfusion phase only, and 3) membrane injury accompanying ischemia and reperfusion may occur th rough fundamentally different mechanisms, of which only the latter is iron dependent.