Sodium Homeostasis Dynamically Regulates Sinoatrial Node Pacemaker Activity

Abstract

The role of Na+ homeostasis in cardiac pacemaking is not well established. Blocking of the Na+-K+ ATPase (NKA) to raise intracellular Na+ concentration ([Na+]i) in ventricular myocytes, thereby increasing Ca2+ load, is widely used to improve cardiac inotropy in congestive heart failure patients. However, NKA-blocking agents have a narrow therapeutic window, as excessive Ca2+ accumulation is pro-arrhythmic and decreases lusitropy. Here, we optimize an existing mathematical model of the mouse sinoatrial node (SAN) cell based on our extensive dataset of electrophysiological experiments (including cell-to-cell variability). Using an established population-based approach, we investigate the consequences of increased [Na+]i on pacemaker function. Model parameter sensitivity analysis reveals that NKA modulation impacts Na+ and Ca2+ homeostasis, as well as several action potential characteristics. NKA dynamically modulates cell automaticity: upon partial NKA inhibition SAN firing rate instantaneously increases, due to the direct effect on the membrane potential dynamics. Over time, reduced Na+ extrusion causes slow [Na+]i accumulation, paralleled by an increase in Ca2+ load, and SAN cell firing rate. We show that this positive chronotropic effect can be drastically reversed. In fact, when simulating stronger NKA inhibition, excessive [Na+]i and thus Ca2+ overload cause loss of automaticity. Logistic regression analysis highlights that perturbations in conductances of L-type Ca2+ current, hERG K+ current, and background Na+ current, and NKA maximal transport rate induce the most pronounced effects on the probability that the cell will stop firing. These parameters are also those maximally influencing [Na+]i regulation as shown in the sensitivity analysis. Hence, by confirming that [Na+]i has a fundamental role in the regulation of cell automaticity, our study suggests that a detailed characterization of Na+ homeostasis in isolated SAN myocytes is essential to fully understand cardiac pacemaker function.