Dynamic regulation of pacemaker activity by the Na⁺-K⁺ pump

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 ventricles, thereby reducing Ca²⁺ removal by the Na⁺-Ca²⁺ exchanger (NCX), is widely used to improve cardiac inotropy in patients with congestive heart failure. However, NKA-blocking agents have a narrow therapeutic window, and cardiotoxic effects are common, as excessive Ca²⁺ accumulation is pro-arrhythmic and decreases lusitropy. Here, we updated an existing mathematical model of the mouse sinoatrial node (SAN) myocyte to determine the effects of increasing [Na⁺]_i on pacemaker cell function, and test whether high [Na⁺]_i levels have disrupting effects similar to those of cardiac glycosides in the ventricle. Model parameter sensitivity analysis revealed that NKA modulation impacts Na⁺ and Ca²⁺ homeostasis, as well as several action potential (AP) characteristics. NKA dynamically modulates cell automaticity: upon NKA inhibition SAN firing rate instantaneously increases, due to direct effects on membrane potential (Em) dynamics, and slowly continues to increase over time, while Na⁺ and Ca²⁺ accumulate. Simulations of various degrees of block showed that Na⁺ overload can even stop SAN firing. Thus [Na⁺]_i plays a fundamental role in the regulation of pacemaker activity.