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 Ca
²⁺
removal by the Na
⁺
-Ca
²⁺
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 Ca
²⁺
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 Ca
²⁺
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 Ca
²⁺
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.