DOXORUBICIN CARDIOTOXICITY IN THE RAT - COMPARISON OF ELECTROCARDIOGRAM, TRANSMEMBRANE POTENTIAL, AND STRUCTURAL EFFECTS

  • 1 January 1984
    • journal article
    • research article
    • Vol. 6  (1) , 186-200
Abstract
The dose-, schedule- and time-dependent effects of doxorubicin (DXR) [an antineoplastic drug] on the rat ECG were studied and ECG alterations related to cellular transmembrane potential (TMP) changes and ultrastructural changes in preparations isolated from DXR-treated animals. DXR was administered i.p. toneally at 1, 2 and 4 mg/kg (all 5 times/wk) or 5 mg/kg once/wk up to a cumulative dose of 20 mg/kg, or 2 mg/kg daily for 5 days for a cumulative dose of 10 mg/kg. Posttreatment deaths were due to acute toxicity (bone marrow suppression) or congestive cardiomyopathy (8-14 wk after the end of dosing). The most consistent ECG changes observed with DXR treatment (> 10 mg/kg cumulative dose) were a reversible prolongation of the QRS complex and a progressive lengthening of the Q.alpha.T interval; changes in R-, S- and T-wave voltages were more variable. ECG toxicity was more pronounced when the drug was given on a weekly schedule. On the cellular level, DXR treatment led to a decrease in .ovrhdot.Vmax, with a slight increase or no change in resting potential, and a marked prolongation in action potential duration at the 50 and 75% repolarization levels. The ECG and TMP changes were accompanied by ultrastructural changes that increased in severity during the posttreatment period. These data further support the usefulness of the rat ECG in anthracycline cardiotoxicity studies.