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REPEATED TREATMENTS WITH DOXORUBICIN CAUSES ELECTROCARDIOGRAM (ECG) CHANGES AND INCREASED VENTRICULAR PREMATURE BEATS IN WISTAR-KYOTO (WKY) RATS
HAZARI, M. S., N. HAYKAL-COATES, D. W. WINSETT, A. P. CARLL, D. L. COSTA, AND A. FARRAJ. REPEATED TREATMENTS WITH DOXORUBICIN CAUSES ELECTROCARDIOGRAM (ECG) CHANGES AND INCREASED VENTRICULAR PREMATURE BEATS IN WISTAR-KYOTO (WKY) RATS. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
The purpose of this study was to examine the effects of repeated administration of DOX on ECG and several biomolecular parameters in the heart and lungs of WKY rats.
Doxorubicin (DOX) is a widely used anthracycline anti-neoplastic drug used to treat tumors. However it has been implicated in irreversible cardiac toxicity via the generation of a proxidant semiquinone free radical, which often results in cardiomyopathy and changes in the ECG. Acute cardiotoxic effects include decreased contractility and electrophysiolological abnormalities such as T-wave flattening, and ST and QT elongation. The purpose of this study was to examine the effects of repeated administration of DOX on ECG and several biomolecular parameters in the heart and lungs of WKY rats. Male rats were anesthetized and surgically implanted with radiotelemeters for the continuous monitoring of heart rate (HR) and ECG. Following recovery, rats received either DOX (1.25mg/kg, 2.5mg/kg or 5mg/kg) or vehicle intraperitoneally once a week for three weeks. Rats were sacrificed 24hrs after the final dose for the collection of bronchoalveolar lavage (BAL) and whole blood, and measurement of hearts weights. ECG for each animal was analyzed for the entire duration of the experiment. DOX caused a dose-related decrease in body weight, heart weight, plasma protein, and superoxide dismutase levels, and an increase in BAL protein and albumin. Treatment with 2.5mg/kg and 5mg/kg of doxorubicin caused prolonged QRS, QT and ST intervals, and a decrease in T-wave amplitude. Rats treated with DOX, particularly with 5mg/kg, also had a higher frequency of ventricular premature beats (VPB) and there was evidence of T-wave notching and periods of sinus tachycardia. DOX caused cardiomyopathy resulting in both cardiac and pulmonary changes. These findings suggest that the ECG is a sensitive indicator of oxidative injury to the myocardium and thus altered ECG may have utility as a biomarker of myocardial oxidant effects. Supported by Curriculum in Toxicology/UNC Grant T32-ES07126. (This abstract does not reflect EPA policy.)