Modelling effects of sotalol on action potential morphology using a novel markov model of the HERG channel

Abstract

In this paper, we present a simulation study of the effects of Sotalol, a known anti-arrhythmic drug, on the rapid delayed rectifier potassium current (IKr). The current is encoded by the Human Ether-a-go-go Related Gene (HERG), which plays a major role in repolarization in mammalian ventricles. HERG is also the target of class III anti-arrhythmic drugs, such as Sotalol. Due to its unique structure and electrophysiological qualities, non-cardiac drugs readily bind with residues inside HERG’s intracellular cavity. A novel Markov model was developed to model Sotalol’s interaction with HERG. The model was validated using experimental data from HERG expressed in Human Embryonic Kidney (HEK) cells and integrated into the ten Tusscher (2006) human ventricular cell model. The simulation results show that an increase in Sotalol concentration decreases the overall conductance of IKr over time, resulting in prolongation of the action potential duration. This effect is larger in mid-myocardial than in endocardial and epicardial cells. Therefore, Sotalol-induced effects on cardiac repolarization may result in enhanced transmural dispersion of repolarization in the ventricles, and also in changes in the T wave.