Effects of the antiarrhythmic drug dofetilide on myocardial electrical activity: a computer modelling study

Dofetilide selectively inhibits the rapid component of the delayed potassium current (I_Kr). In this work, a mathematical model of dofetilide effects on I_Kr has been developed. This model has been incorporated to the Luo and Rudy (II) model of guinea pig ventricular action potential and the effect of different dofetilide concentrations on the action potential characteristics has been studied. Our results show that the steady-state block of I_Kr is dose-dependent with a block of 10%, 53% and 92% for 1 nM, 10 nM and 100 nM of dofetilide respectively (IC₅₀=8.7 nM). This increment of I_Kr block when the concentration increases induces a prolongation of APD also in a dose-dependent way. We observed prolongations of APD₉₀ of 13% and 28% for 10 nM and 100 nM of dofetilide respectively. In agreement with experimental results, the interaction between dofetilide and the receptor in the channel presents slow kinetics and reverse use-dependence in our model.