Role of Muscle in Regulating Extracellular [K⁺]

There is a positive association between diets rich in potassium, control of blood pressure, and prevention of stroke. Extracellular [K⁺] is regulated closely to maintain normal membrane excitability by the concerted regulatory responses of muscle and kidney. Although kidney is responsible for ultimately matching K⁺ output to K⁺ intake each day, muscle contains more than 90% of the body’s K⁺ and can buffer changes in extracellular fluid [K⁺] by either acutely taking up extracellular fluid K⁺ or releasing intracellular fluid K⁺ from muscle. It long has been assumed that the changes in muscle K⁺ transport are a function of sodium pump (Na,K-adenosine triphosphatase [Na, K-ATPasel]) abundance, especially that of the α2 isoform, which predominates in skeletal muscle. To test the physiologic significance of changes in muscle Na,K-ATPase expression, we developed the K⁺ clamp, which measures insulin-stimulated cellular K⁺ uptake in vivo in the conscious rat. By using the K⁺ clamp we discovered that significant insulin resistance to cell K⁺ uptake occurs as follows: (1) early in K⁺ deprivation before a decrease in muscle sodium pump pool size, and (2) during glucocorticoid treatment, which increases muscle Na,K-ATPase α2 levels greater than 50%. We also discovered that adaptation of renal and extrarenal K⁺ handling to altered K⁺ balance often occurs without changes in plasma [K⁺], supporting a feedforward mechanism involving K⁺ sensing in the splanchnic bed and adjustment of K⁺ handling. These findings establish the advantage of combining molecular analyses of Na,K-ATPase expression and activity with systems analyses of cellular K⁺ uptake and excretion in vivo to reveal regulatory mechanisms operating to control K⁺ homeostasis.

Keywords:  Na,K-ATPase , K clamp , hypokalemia , insulin , ion homeostasis