Theoretical study of L‐type Ca2+ current inactivation kinetics during action potential repolarization and early afterdepolarizations

The L-type Ca2+ current (ICa) plays an important role in regulation of excitation–contraction coupling and development of cardiac arrhythmias. We studied theoretically ICa inactivation and the relative contributions of voltage-dependent inactivation (VDI) and Ca2+-dependent inactivation (CDI) to total inactivation, and we present an improved mathematical model of rabbit ventricular ICa. The model proposes that inactivation observed when Ba2+ is the charge carrier includes a small contribution from ion-dependent inactivation (in addition to pure VDI), usually neglected by other modelling studies. The model, identified and validated against a broad set of experimental data, is applied to study the relative roles of VDI and CDI (and the relative contributions of different Ca2+ sources to total CDI) during normal and abnormal repolarization. The model predicts that CDI is crucial for repolarization, and that impairment of CDI may be arrhythmogenic by affecting intracellular Ca2+ cycling, through its effect on the ICa time course and Na+–Ca2+ exchanger activity. Abstract Sarcoplasmic reticulum (SR) Ca2+ release mediates excitation–contraction coupling (ECC) in cardiac myocytes. It is triggered upon membrane depolarization by entry of Ca2+ via L-type Ca2+ channels (LTCCs), which undergo both voltage- and Ca2+-dependent inactivation (VDI and CDI, respectively). We developed improved models of L-type Ca2+ current and SR Ca2+ release within the framework of the Shannon–Bers rabbit ventricular action potential (AP) model. The formulation of SR Ca2+ release was modified to reproduce high ECC gain at negative membrane voltages. An existing LTCC model was extended to reflect more faithfully contributions of CDI and VDI to total inactivation. Ba2+ current inactivation included an ion-dependent component (albeit small compared with CDI), in addition to pure VDI. Under physiological conditions (during an AP) LTCC inactivates predominantly via CDI, which is controlled mostly by SR Ca2+ release during the initial AP phase, but by Ca2+ through LTCCs for the remaining part. Simulations of decreased CDI or K+ channel block predicted the occurrence of early and delayed afterdepolarizations. Our model accurately describes ECC and allows dissection of the relative contributions of different Ca2+ sources to total CDI, and the relative roles of CDI and VDI, during normal and abnormal repolarization.