ToxSci Advance Access originally published online on April 30, 2009
Toxicological Sciences 2009 110(1):224-234; doi:10.1093/toxsci/kfp092
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Continuous Electrocardiogram Reveals Differences in the Short-Term Cardiotoxic Response of Wistar-Kyoto and Spontaneously Hypertensive Rats to Doxorubicin
* Experimental Toxicology Division
Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at Experimental Toxicology Division, USEPA, 109 Alexander Drive, B143-01, Research Triangle Park, NC 27711. Fax: (919) 541-0034. E-mail: hazari.mehdi{at}epa.gov.
Received February 24, 2009; accepted April 22, 2009
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Abstract |
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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 with 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 1-week baseline and throughout the experimental period until rats were sacrificed 24 h 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 with 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.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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