Estimating Contribution Of Individual Ionic Components To The Cardiac Pacemaker Potential

Abstract

Action potentials are generated by complicated interactions of various ionic channels and transporters through variations of membrane potential and/or the intracellular Ca2+ concentrations. It is still difficult to isolate the contribution of individual current from the secondary effect of modified channel activities. For example, if an ion channel is blocked, the pacemaker activity is drastically changed from the control time course. We have proposed a theoretical method to visualize the contribution of each current in the simulation study. Namely an instantaneous equilibrium potential, the lead potential (VL), was calculated along the time course of pacemaker potential. VL is given as, VL = (ΣGXEX - ΣIpump)/ΣGX,where GX and EX are whole cell membrane conductance and reversal potential for ion X. Contribution of a given current system is evaluated by comparing VL obtained by fixing the gating parameter of a given current system with the control VL. In the present study, the gating parameters are fixed during slow diastolic depolarization and action potential repolarization.It is revealed that the initial phase of the slow diastolic depolarization is mostly attributable to deactivation of the rapid component of the delayed rectifier K+ current (IKr). Then, the major inward currents, the hyperpolarization-activated current (If) and the sustained inward current (Ist) are activated to depolarize the membrane further to reach the threshold potential of the L-type Ca2+ channel current (ICaL). Activation of ICaL initiates generation of action potentials. Deactivation of ICaL and activation of IKr and the slow component of the delayed rectifier K+ current (IKs) occur during repolarizing phase. Contribution of Ist activation to the repolarization is much larger than that of If. Activation of If, Ist, ICaL and IKs through phosphorylation during β1-adrenergic stimulation failed to modify each contribution dramatically.