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.

Excess Protein O-GlcNAcylation Links Metabolic Derangements to Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

“…First, the relative increase in tubulin, the individual subunits of microtubules, in PAB ( Supplemental Figure S6 ) are less than what we observed in MCT rats [ 31 ], and there may be a threshold of microtubule remodeling needed for a pathological response. Second, it is possible that chronic colchicine treatment and microtubule depolymerization could have adverse effects on cardiac function as a previous manuscript showed high dose colchicine causes cardiac conduction abnormalities, however at much higher doses than we used [ 32 ]. While there are strong data linking microtubule remodeling to impaired cardiac contractility [ 33 , 34 , 35 ], perhaps the less prominent microtubule phenotype of PAB rats cannot be enhanced with colchicine because microtubule remodeling is not the driving force of this mild right ventricular dysfunction phenotype.…”

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…A sample size of 25 to 30 was targeted for 3 reasons: there were 3 groups in the analysis, to reduce effects of the heterogeneity with colchicine treatment, and to account for possible deaths during the experimental time frame. The dosing scheme was implemented as similar doses were shown to depolymerize the microtubule cytoskeleton in cardiomyocytes in rats23, 24 but less than doses that are associated with significant cardiotoxicity in rats 25. Four weeks after MCT injection was the end point of the study because a previous study had shown that time frame was associated with severe pulmonary hypertension 21…”

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

“…The study indicated that ephedrine isolated from Ephedra sinica Stapf could trigger a range of cardiovascular toxicities, including myocarditis, arrhythmias, myocardial infarction, cardiac arrest, heart failure, and sudden death ( Samenuk et al, 2002 ; Adamson et al, 2004 ; Naik and Freudenberger, 2004 ; Nyska et al, 2005 ). Colchicine derived from Colchicum autumnale has been proved to impair impulse formation and conduction ( Tochinai et al, 2014 ). Another study suggested that colchicine could directly damage cardiac endothelial cells to induce cardiotoxicity ( Mikaelian et al, 2010 ).…”