Development and Validation of an In Silico Rabbit Purkinje Cell Action Potential Model: A Step Towards a Drug Safety Testing Tool

摘要

Companies and regulators evaluate compounds' cardiac safety commonly through in-vitro assays involving cardiac cells. Rabbit cardiac Purkinje Cells (RPCs) are very sensitive to drug effects such as Action Potential Duration (APD) alteration by ion channel block. Our objective is to create a novel RPC model calibrated with the latest experimental data. We developed a new RPC model using Pan-Rudy‘s Canine Purkinje cell model as a framework. We adapted important parameters, namely, size, ion fluxes and conductances. We also included a sodium current Markovian formulation to account for its recently increased importance. Variables were adjusted to match the main experimentally observed RPCs features. Steady-state was reached by pacing the model for 1500 seconds at different Basic Cycle Lengths (BCLs). The model was validated by extracting data from experimental sources. Results show overall agreement with the literature with improvements to previous models. In conclusion, we improved and successfully validated an RPC model. This work paves the way towards a reliable in-silico tool for testing drug effects on RPCs.