Dual mechanisms of cardiotoxicity induced by cisapride

The gastrointestinal prokinetic drug, cisapride, has been associated with the development of the potentially lethal form of ventricular arrhythmia known as torsades de pointes (TdP), and its clinical use has recently become highly restricted as a result of this association. To evaluate the direct cardiac actions of cisapride, we measured various ECG parameters and ion channel densities recorded from isolated rabbit hearts and ventricular cardiomyocytes, respectively, in the presence and absence of various concentrations of cisapride. We found that cisapride blocks ventricular repolarization (QT-lengthening and I_Kr blockade) at concentrations as low as 0.1 μM, while ventricular depolarization (QRS widening and use-dependent I_Na blockade) was inhibited at cisapride concentrations ≥ 1 μM. These dual mechanisms of ion channel blockade likely account for the severe cardiotoxicity observed in response to high concentrations of cisapride.