Effects of doxorubicin on cardiac contractility, glutathione and ldpid peroxidation

It has been proposed that the cardiotoxicity of doxorubicin (DOX) is mediated via oxidative mechanisms. Experiments examined this hypothesis by determining if effects of DOX-treatment on contractility are paralleled by changes in glutathione levels or lipid peroxidation (as monitored via levels of malonyldialdehyde, MDA). Rats were injected with a single dose of 4, 6 or 8 mg/kg DOX (or solvent) 3 or S weeks before tissue isolation. Contractility was monitored in trial (AM) and papillary (PM) muscle that was bathed in Krebs-Henseleit solution (30°C). Glutathione and MDA were monitored in ventricular tissue using standard assays. ' DOXtreatment elicited decreases in rest-potentiated developed tension and the isoproterenol-induced positive inotropic effect in both AM and PM. The force-frequency relationship showed a DOX-associated decrease in basal developed tension in AM at frequencies between 0.1 and 0.5 Hz; however, PM showed no differences in basal developed tension at any frequency from 0.1 to 4.S Hz. Glutathione levels were decreased, while MDA was increased in ventricular myocardium by DOX-treatment. There were no differences in tissues isolated 3 or 5 weeks after injection of DOX. These data support the hypothesis that the cardiomyopathy elicited by DOX is mediated, at least in part, by oxidative damage.