Intracellular Na⁺ regulation in cardiac myocytes

Intracellular [Na⁺] ([Na⁺]_i) is regulated in cardiac myocytes by a balance of Na⁺ influx and efflux mechanisms. In the normal cell there is a large steady state electrochemical gradient favoring Na⁺ influx. This potential energy is used by numerous transport mechanisms, including Na⁺ channels and transporters which couple Na⁺ influx to either co- or counter-transport of other ions and solutes. Six sarcolemmal Na⁺ influx pathways are discussed in relatively quantitative terms: Na⁺ channels, Na⁺/Ca²⁺ exchange, Na⁺/H⁺ exchange, Na⁺/Mg²⁺ exchange, Na⁺/HCO₃^- cotransport and Na⁺/K⁺/2Cl^- cotransport. Under normal conditions Na⁺/Ca²⁺ exchange and Na⁺ channels are the dominant Na⁺ influx pathways, but other transporters may become increasingly important during altered conditions (e.g. acidosis or cell volume stress). Mitochondria also exhibit Na⁺/Ca²⁺ antiporter and Na⁺/H⁺ exchange activity that are important in mitochondrial function. These coupled fluxes of Na⁺ with Ca²⁺, H⁺ and HCO₃^- make the detailed understanding of [Na⁺]_i regulation pivotal to the understanding of both cardiac excitation-contraction coupling and pH regulation. The Na⁺/K⁺-ATPase is the main route for Na⁺ extrusion from cells and [Na⁺]_i is a primary regulator under physiological conditions. [Na⁺]_i is higher in rat than rabbit ventricular myocytes and the reason appears to be higher Na⁺ influx in rat with a consequent rise in Na⁺/K⁺-ATPase activity (rather than lower Na⁺/K⁺-ATPase function in rat). This has direct functional consequences. There may also be subcellular [Na⁺]_i gradients locally in ventricular myocytes and this may also have important functional implications. Thus, the balance of Na⁺ fluxes in heart cells may be complex, but myocyte Na⁺ regulation is functionally important and merits focused attention as in this issue.