This study was designed to clarify the mechanism of ischemia-reperfusion injury to skeletal muscle using long-acting polyoxyethylene-modified superoxide dismutase (SOD-POE) in rats. The gastrocnemius muscles of male Lews rats were investigated. Tissue levels of ATP decreased to 20% of nonischemic values after 3 h ischemia and returned to 94% after 1 h reperfusion. In contrast, they decreased to 3.5% after 4 h ischemia and remained at 20% after 1 h reperfusion. Although SOD-POE did not affect the decrease of ATP during ischemia, it improved significantly the recovery of ATP: 28%. Tissue levels of lipid peroxides (LPO) after 3 h ischemia and 1 h reperfusion did not change significantly compared with the nonischemic levels (0.71 ± 0.32 nmol/mg protein, mean ± SD). They showed no increase after 4 h ischemia, but increased explosively after 1 h reperfusion (2.15 ± 0.73 nmol/mg protein). SOD-POE did not affect LPO levels during ischemia but prevented the increase of LPO significantly after reperfusion (0.98 ± 0.25 nmol/mg protein). Xanthine oxidase activity did not increase after 3 h ischemia (22.3 ± 7.0 mU/g) compared with the nonischemic values (17.6 ± 10.0 mU/g). In contrast, it increased 2.5-fold after 4h ischemia (50.1 ± 13.7 mU/g) and remained at a significantly high level after 1 h reperfusion. SOD-POE did not affect xanthine oxidase activity during ischemia and reperfusion. These results suggest that lipid peroxidation by superoxide radicals produced by xanthine oxidase is a contributory factor to ischemia-reperfusion injury to skeletal muscle, and the clinical application of SOD-POE might be expected.
Polyoxyethylene‐modified superoxide dismutase (SOD‐POE) is a newly developed long‐acting superoxide dismutase. Adriamycin (ADR) and mitomycin C (MMC) generate superoxide, which contributes to their cytocidal effects or side effects. We examined whether SOD‐POE could prevent the side effects induced by superoxide generated by antitumor agents, and the following results were obtained. SOD‐POE did not influence the antitumor effects of ADR and MMC either in vitro or in vivo, but prevented the toxic death of BALB/c, nu/nu male mice caused by overdoses of ADR or MMC. As for its effective sites, SOD‐POE prevented a decrease in the specific activity of rotenone‐sensitive NADH‐ubiquinone oxidoreductase (complex I) in heart muscle mitochondrial respiratory chain function in BALB/c male mice administered 10 mg/kg ADR, and prevented damage to the sarcoplasmic reticulum and mitochondria of mouse heart muscle by ADR as observed by electron microscopy. Furthermore, SOD‐POE prevented bone marrow suppression induced by MMC in Donryu rats. The above results suggest that combination chemotherapy with SOD‐POE would make it possible to increase the maximum permissible doses of antitumor agents, improving the efficacy of these agents.
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