Cardiotoxic changes of colchicine intoxication in rats: electrocardiographic, histopathological and blood chemical analysis.
The microtubule inhibitor colchicine is cardiotoxic and is suggested to impair impulse formation and conduction. However, little is known about the electrocardiographic (ECG) changes induced by colchicine in experimental animals and the detailed pathogenesis of its cardiotoxicity. Therefore, we analyzed cardiotoxicity in colchicine-treated rats using electrocardiographic, histopathological and blood-chemistry approaches. A telemetry device for transmitting ECG data was implanted into male Crl:CD(SD) rats, and ECG tracings were obtained. At 6 weeks of age, 1.25 mg/kg colchicine was injected intravenously once daily for 2 consecutive days, and ECG waveforms and heart rate variability were analyzed. Furthermore, 1.25 mg/kg colchicine or vehicle was injected for 1 or 2 consecutive days in other rats at 6 weeks of age. One day after the final dosing, heart and blood samples were taken for histopathological and bloodchemical examination. ECG analysis revealed a prolonged RR interval, QRS duration, PR interval and QT interval. Heart rate variability analysis showed an increase in high frequency (HF) components as an index of parasympathetic nervous activity. In blood chemical examinations, colchicine induced high levels of parameters of cardiac injury and low levels and/or variations in Ca, inorganic phosphorus, potassium and chloride. Histopathologically, colchicine-treated rats showed eosinophilic granular degeneration and cytoplasmic vacuolation of ventricular myocardial cells but no remarkable change in the atrioventricular node. Not only blood chemical and histopathological changes but also ECG changes were induced in colchicine-treated rats, which indicated a decrease in myocardium excitability and conductivity, and these changes might be related to increased parasympathetic nervous activity and low blood Ca levels.
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Ryota
R
Tochinai
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Katsuya
K
Suzuki
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Yuriko
Y
Nagata
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Minoru
M
Ando
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Chie
C
Hata
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Kayoko
K
Komatsu
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Tomo
T
Suzuki
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Kazumi
K
Uchida
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Shoichi
S
Kado
Safety Research Department, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan.
Kimiyuki
K
Kaneko
Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Masayoshi
M
Kuwahara
cardiotoxicity; colchicine; electrocardiogram; heart rate variability; parasympathetic nerve; rat