Doxorubicin cardiotoxicity in the rat: comparison of electrocardiogram, transmembrane potential, and structural...

We have evaluated the dose-, schedule-, and time-dependent effects of doxorubicin (DXR) on the rat electrocardiogram (ECG) and have related ECG alterations to cellular transmembrane potential (TMP) changes and ultrastructural changes in preparations isolated from DXR-treated animals. DXR was administered intraperitoneally at 1, 2, and 4 mg/kg (all five times per week) or 5 mg/kg once per week 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 weeks after the end of dosing). The most consistent ECG changes observed with DXR treatment (greater than 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 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. Our data further support the usefulness of the rat ECG in anthracycline cardiotoxicity studies.