title: Continuous electrocardiogram reveals differences in the short-term cardiotoxic response of Wistar-Kyoto and spontaneously hypertensive rats to doxorubicin.
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 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 (T(co)) 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 T(co) of high DOX SH rats. In the ECG, SH rats had prolonged baseline PR intervals and QT(c) when compared with WKY rats. All DOX-treated WKY rats subsequently developed PR interval prolongation; however only those treated with high DOX had increased QT(c). 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.
authors.affiliation: Experimental Toxicology Division, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. hazari.mehdi@epa.gov
authors.forename: Mehdi S
authors.initials: MS
authors.lastname: Hazari
authors.forename: Najwa
authors.initials: N
authors.lastname: Haykal-Coates
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Winsett
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Costa
authors.forename: Aimen K
authors.initials: AK
authors.lastname: Farraj
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004317:Doxorubicin / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013686:Telemetry
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin