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

摘要

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.