DOXORUBICIN TOXICITY IN PERFUSED RAT-HEART - DECREASED CELL-DEATH AT LOW OXYGEN-TENSION

The purpose of these studies was to test whether O2 tension influences cardiotoxicity due to doxorubicin. Isolated hearts were perfused by the method of Langendorff at constant pressure with Krebs-Henseleit buffer saturated with 5% CO2 and either 95% or 20% O2. Toxicity due to doxorubicin was evaluated from changes in heart rate and from uptake of trypan blue by nonviable nuclei. Heart rate was stable in control hearts perfused at 95% O2 for 30 minutes but decreased in hearts perfused at 20% O2. Doxorubicin (30-mu-M) increased O2 uptake due to redox cycling by approximately 75-mu-mol/g/hr at 95% O2 but had no effect in hearts perfused at 20% O2. Heart rate decreased during 30 minutes of perfusion with doxorubicin and 95% or 20% O2, with greater decreases occurring with 95% than 20% O2 compared with values for the respective untreated controls. Irreversible cell damage indexed from uptake of vital dye due to doxorubicin was threefold greater than control at 95% O2 but was not different from control at 20% O2. These data are consistent with the hypothesis that O2 tension is an important determinant of toxicity due to doxorubicin.