A CAUSATIVE ROLE FOR REDOX CYCLING OF MYOGLOBIN AND ITS INHIBITION BYALKALINIZATION IN THE PATHOGENESIS AND TREATMENT OF RHABDOMYOLYSIS-INDUCED RENAL-FAILURE

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We test ed the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F-2-isoprostanes, potent renal vasoeonstrictors f ormed during lipid peroxidation. In low density lipoprotein (LDL), myo globin induced a 30-fold increase in the formation of F-2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl form s of myoglobin, In an animal model of rhabdomyolysis, urinary excretio n of F-2-isoprostanes increased by 7.3-fold compared with controls. Ad ministration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F-2-isopr ostanes by similar to 80%, EPR and UV spectroscopy demonstrated that m yoglobin was deposited in the kidneys as the redox competent ferric my oglobin and that it's concentration was not decreased by alkalinizatio n, Kinetic studies demonstrated that the reactivity of ferryl myoglobi n, which is responsible for inducing lipid peroxidation, is markedly a ttenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in t he renal failure of rhabdomyolysis and suggest that the protective eff ect of alkalinization may be attributed to inhibition of myoglobin-ind uced lipid peroxidation.