Model-based analysis of the effects of thioridazine enantiomers on the rabbit papillary action potential

Abstract

Aims: We investigated mechanisms underlying the effects of the thioridazine enantiomers on the rabbit papillary action potential duration (AP, APD).Methods: An adapted computational model of the rabbit ventricular action potential was used to carry out a model-based analysis of transmembrane AP recordings from isolated right ventricular papillary muscles from 21 rabbits in four groups: control, (-)-thioridazine, (+)-thioridazine, and racemate. Drug effects were determined using an inverse method and a forward method. Effects were modeled by inhibition of the IKr and I CaL currents.Results: Simultaneous inhibition of I Kr and I CaL resulted in a more accurate description of the observed drug effects than could I Kr inhibition alone. The following values of I Kr inhibition at 10 mg L -1 were determined. Forward method: Racemate = 45%, (-)-thioridazine = 0%, and (+)-thioridazine = 85%. Inverse method: (-)-thioridazine = 35%, (+)-thioridazine = 80%.Conclusion: I Kr inhibition accurately described the observed APD prolongation, and the identified levels of I Kr inhibition were plausible when compared to literature. Both methods found (-)-thioridazine to cause less I Kr inhibition than (+)-thioridazine or the racemate. These results indicate that the prolonging effects observed in the experiment may be related to I Kr inhibition.