Role of Ca2+-dependent Cl- current on delayed afterdepolarizations. A simulation study.

Abstract

Calcium-dependent chloride current (I (Cl,Ca)) is the second component (I (to2)) of the transient outward current (I (to)) that provokes the action potential (AP) phase 1 repolarization. This current contributes to the transient inward current (I (ti)) that generates delayed afterdepolarizations (DAD) in several pathological conditions. The present work uses a computer AP model of rabbit atrial myocyte and a one-dimensional (1D) tissue model of 400 cells to study the role of I (Cl,Ca) on the generation of DAD and triggered activity under calcium-overload conditions. A mathematical model describing the dependence of I (Cl,Ca) on intracellular Ca(2+) is proposed. This model takes into account the experimentally recorded characteristics of I (Cl,Ca): (1) calcium dependence, (2) voltage-dependent inactivation, and (3) I-V field-diffusion relation. Our results support the hypothesis that I (Cl,Ca) plays an important role in action potential repolarization, mainly at high frequencies. In the calcium-overload conditions tested in this work, I (Cl,Ca) represents between 28% and 44% of the total I (ti) that provokes DADs. Our simulations also show that the blockage of I (Cl,Ca) reduces the calcium overload range in which DADs provoke triggered activity.