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ToxSci Advance Access published online on April 30, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp092
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Continuous electrocardiogram reveals differences in the short-term cardiotoxic response of Wistar-Kyoto and Spontaneously Hypertensive rats to doxorubicin

Mehdi S. Hazari*, Najwa Haykal-Coates*, Darrell W. Winsett*, Daniel L. Costa§ and Aimen K. Farraj*

* Experimental Toxicology Division § Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, 27711

Corresponding author: Mehdi S. Hazari, Experimental Toxicology Division, USEPA, 109 Alexander Drive, B143-01; Research Triangle Park, NC 27711; (Phone: 919-541-4588; Fax: 919-541-0034; email: hazari.mehdi{at}epa.gov)

Received February 24, 2009; revision received April 21, 2009; accepted April 22, 2009


  Abstract

Electrocardiography (ECG) is one of the standard technologies used to monitor and assess cardiac function, and provide insight into the mechanisms driving myocardial pathology. Increased understanding of the effects of cardiovascular disease on rat ECG may help make ECG assessments in rat toxicology studies routine, thus facilitating continuous measurement of functional decrements associated with cardiotoxicant exposure. These studies seek to test the hypothesis that hypertensive rats are more susceptible to the short-term cardiotoxic effects of doxorubicin (DOX) when compared to normotensive rats with respect to continuously measured ECG endpoints. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats surgically implanted with radiotelemeters were treated once a week for three weeks with either vehicle, 1.25 (low), 2.5 (medium), or 5 (high) mg/kg DOX (i.p.). ECG, heart rate (HR), and core body temperature (Tco) were continuously monitored during the one-week baseline and throughout the experimental period until rats were sacrificed 24hrs after the third injection. DOX prevented normal body weight gain in both strains and significantly decreased diurnal HR and Tco of high DOX SH rats. In the ECG, SH rats had prolonged baseline PR intervals and QTc when compared to WKY rats. All DOX-treated WKY rats subsequently developed PR interval prolongation; however only those treated with high DOX had increased QTc. DOX caused an increase in ST interval in SH rats, and resulted in ECG morphology changes. The number of arrhythmias due to DOX was increased in both strains. In conclusion, ECG analysis can reveal underlying cardiovascular disease as a risk factor in the heart's response to toxicant-induced injury in the rat; and be a valuable tool to evaluate baseline vulnerability and assess cardiotoxicity.

Key Words: electrocardiogram; doxorubicin; cardiotoxicity; hypertension.

coates.najwa{at}epa.gov; winsett.darrell{at}epa.gov; costa.dan{at}epa.gov; farraj.aimen{at}epa.gov


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