Dynamics of sodium current mediated early afterdepolarizations

Early afterdepolarizations (EADs) have been attributed to two primary mechanisms: 1) recovery from inactivation of the L-type calcium (Ca) channel and/or 2) spontaneous Ca release, which depolarizes the membrane potential through the electrogenic sodium-calcium exchanger (NCX). The sodium (Na) current (I(Na)), especially the late component of the Na current, has been recognized as an important player to set up the conditions for EADs by reducing repolarization reserve and increasing intracellular Na concentration, which leads to Ca overload. However, I(Na) itself has not been considered as a direct initiator of EADs. A recent experimental study by Horvath et al. has shown that the amplitude of the late component of the Na current is as large as potassium (K) and Ca currents (∼1 pA/pF). This result suggests that I(Na) by itself can exceeds the sum of outward currents and depolarize the membrane potential. In this study, we show that I(Na) can also directly initiate EADs. Mathematical analysis reveals a fundamental dynamical origin of EADs arising directly from the Na channel reactivation. This system has three fixed points. The dynamics of the I(Na) mediated EAD oscillation is different from that of the membrane voltage oscillation of the pacemaker cell, which has only one fixed point.