Voltage gated ion channels blockade is the underlying mechanism of BIMU8 induced cardiotoxicity.

BIMU8 is a 5-HT4 receptor agonist and used as an experimental drug to counteract opioid induced respiratory depression. In preliminary experiments serious disturbances in ECG were observed in anesthetized rabbits which prompted us to explore the underlying cause of BIMU8 induced abnormal changes in ECG recordings. Electrophysiological experiments were performed on HEK-293 cells expressing hERG, Ca1.2 and Na1.5 ion channels. In whole-cell recordings BIMU8 effectively blocked these three channels, with IC values of 0.06±0.05, 1.46±0.26 and 4.66±0.58μM for hERG, Na1.5 and Ca1.2, respectively. Additionally it also produced a hyperpolarizing shift of 3.27mV in half maximal activation and 12.87mV in fast inactivation of Na1.5 channel. These experimental findings indicate that BIMU8 is a potent blocker of hERG, Na1.5 and Ca1.2 cardiac ion channels thus revealing its proarrhythmic potential.