Modeling the Effect of Kv1.5 Block on the Canine Action Potential

A wide range of ion channels have been considered as potential targets for pharmacological treatment of atrial fibrillation. The Kv1.5 channel, carrying the I-kur current, has received special attention because it contributes to repolarization in the atria but is absent or weakly expressed in ventricular tissue. The dog serves as an important animal model for electrophysiological studies of the heart and mathematical models of the canine atrial action potential (CAAP) have been developed to study the interplay between ionic currents. To enable more-realistic studies on the effects of Kv1.5 blockers on the CAAP in silico, two continuous-time Markov models of the guarded receptor type were formulated for Kv1.5 and subsequently inserted into the Ramirez-Nattel-Courtemanche model of the CAAP. The main findings were: 1), time- and state-dependent Markov models of open-channel Kv1.5 block gave significantly different results compared to a time- and state-independent model with a down-scaled conductance; 2), the outcome of Kv1.5 block on the macroscopic system variable APD(90) was dependent on the precise mechanism of block; and 3), open-channel block produced a reverse use-dependent prolongation of APD(90). This study suggests that more-complex ion-channel models are a prerequisite for quantitative modeling of drug effects.