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

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 I_Kr 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 IKr 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 IKr inhibition.