Cardiotoxic changes of colchicine intoxication in rats: electrocardiographic, histopathological and blood chemical analysis

Abstract

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.

Keywords: cardiotoxicity; colchicine; electrocardiogram; heart rate variability; parasympathetic nerve; rat.

Fig. 1.

Time-response curves of the RR interval (A), QRS duration (B), PR interval (C), QT interval (D) and QT-RR plot (E) before and after injections of colchicine. Arrows indicate time points of colchicine injection. White bars and filled bars on horizontal axes indicate the light period and dark period, respectively. Error bars indicate the SE.

Fig. 2.

Time-response curves of the LF/HF ratio (A) and HF power (B) before and after injections of colchicine. The LF/HF ratio is an index of balance between sympathetic and parasympathetic nervous activity, and HF power is an index of parasympathetic nervous activity. Arrows indicate time points of colchicine injection. White bars and filled bars on horizontal axes indicate the light period and dark period, respectively. Error bars indicate the SE.

Fig. 3.

Micrograph of lesions in the hearts of rats treated with colchicine or 5% glucose twice A: Normal left ventricular wall of a rat given 5% glucose. B: Degeneration with eosinophilic granules and vacuolation in sarcoplasm (arrowheads) of myocardial cells and pyknosis, karyorrhexis and mitotic figures (white arrows) of interstitial cells in left ventricular wall of a rat given colchicine. A high magnification view of the eosinophilic granules and vacuolation in sarcoplasm enclosed by a black rectangle is shown in the upper right. C: Almost no cleaved caspase-3-positive cells in the normal myocardium of a rat given 5% glucose. D: Cleaved caspase-3-positive cells (arrows) in the intersititial cells of the myocardium, which showed pyknosis, karyorrhexis and mitotic figures. E: Normal atrioventricular node of a rat given 5% glucose. F: Atrioventricular node of a rat given colchicine with no remarkable findings. E: Normal endocardial cells of a rat given 5% glucose. H: Pyknosis, karyorrhexis and mitotic figures (arrow) of endocardial cells of a rat given colchicine. A, B and D–H: H-E staining, bars = 40 µm. C and D: Immunohistochemical staining for cleaved caspase-3, bars = 40 µm.

Fig. 4.

Micrograph of lesions in the gastrocnemius muscle, liver, kidney and stomach of rats treated with colchicine twice. A: Vacuolation in sarcoplasm (arrows) of the gastrocnemius muscle of a rat treated with colchicine. B: Single-cell necrosis (arrowheads) and increase in mitotic figures (arrows) of midlobular hepatocytes of a rat treated with colchicine. C: Pyknosis (arrowheads) and increase in mitotic figures (arrows) of the tubular epithelium in the kidney of a rat treated with colchicine. D: Pyknosis (arrowheads) of the collecting duct in the kidney of a rat treated with colchicine. E: Pyknosis (arrowheads) and increase in mitotic figures of the mucosal epithelium of the stomach of a rat treated with colchicine. A–E: H-E staining, bars = 40 µm. C and D: Immunohistochemical staining for cleaved caspase-3, bars = 40 µm.