Abstract

Zebrafish is an emerging model to predict the drug induced arrhythmias in human beings. The electrophysiological properties like electrocardiogram (ECG) pattern, ventricular action potential duration (APD) of zebrafish are similar to humans. In the present study, zebrafish model is standardized for the recording of ECG and validated using the positive and the negative control agents such as dofetilide and the chloroquine phosphate respectively. Adult zebrafish (n=6) were immobilized on a wet sponge with a paralytic dose of Pancuronium (0.0025 mg/ml) administered by intraperitoneal route (i.p.). HEPES in E-3 solution was continuously perfused orally for four hours to maintain the fish alive outside the water environment. 29-gauge needle electrodes were placed on the surface of fish to simulate the lead II configuration and the stable baseline ECG was recorded for approximately 10 minutes. Dofetilide (75 μM and 50 μM for male and female fish) and chloroquine phosphate (5000 μM for both sexes) were orally perfused until various pro-arrhythmic endpoints were observed. A decrease in heart rate, bradycardia was observed with dofetilide (24%) whereas chloroquine did not show any effect on heart rate. The QT and the corrected QT intervals prolongation and Torsades de Pointes were observed after dofetilide administration as predicted. Whereas no QT prolongation and no incidences of arrhythmia were observed after chloroquine administration as expected. The results of the drugs used in the current study showed the effects as observed in mammalian species based on the literature references. Therefore it can be concluded that the adult zebrafish model is validated for its use to predict the pro-arrhythmic potential of the new chemical entities or unknown compounds.