Clinical and therapeutic significance of the Na+,K+ pump*

Abstract

1. The Na+,K+-ATPase or Na+,K+-pump, mediating the active transport of Na+ and K+, which was first identified 40 years ago, is a central target for acute and long-term regulation, as well as for therapeutic intervention. Acute stimulation of the Na+,K+-pump in skeletal muscle by insulin, catecholamines, beta2-agonists or theophylline increases the intracellular uptake of K+ and accounts for the hypokalaemia elicited by these agents. Conversely, digitalis intoxication elicits hyperkalaemia via acute inhibition of the Na+, K+-pump. 2. Simple and accurate methods have been developed for the quantification of the total concentration of Na+,K+-pumps in small (0.5-5 mg) fresh or frozen biopsies of human skeletal muscle, myocardium or other tissues. This has allowed the identification of several long-term regulatory changes in the concentration of this transport system in human tissues. In skeletal muscle, upregulation is induced by training, thyroid hormones or glucocorticoids. Downregulation is seen in hypothyroidism, cardiac insufficiency, myotonic dystrophy, McArdle disease, K+ deficiency and after muscle inactivity. 3. Since the skeletal muscles contain one of the major pools of Na+,K+-pumps, these changes are important for the ability to counterregulate the hyperkalaemia elicited by exercise or the ingestion of K+. Moreover, downregulation or inhibition of the Na+, K+-pumps in skeletal muscle interferes with contractile performance. Since digitalis glycosides bind to the Na+,K+-pump, the muscles constitute a large distribution volume for these agents and are therefore an important determinant for their plasma level. 4. In cardiac insufficiency, the decrease in the concentration of Na+, K+-pumps in the myocardium is over a wide range correlated to the concomitant reduction in ejection fraction. The regulatory and pathophysiological changes in the activity and concentration of Na+, K+-pumps are important for the contractile function of skeletal muscle and heart as well as for K+ homoeostasis and the response to digitalization.

Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin

“…The concentrations of Mg, K and Na,K-ATPase observed before chemotherapy were in accordance with earlier studies, and therefore do not indicate an ion derangement in cancer patients when WHO performance status is better than 2 (Elin, 1987;Clausen, 1998). P-Mg was below the lower reference level after therapy in 38% of the patients and a novel observation was that the decrease in P-Mg was accompanied by an E15% loss of muscle Mg and E10% loss of muscle K; mean loss 1.2 and 8.0 mmol kg À1 wet wt.…”

“…Despite a decrease in skeletal muscle K, the Na,K-ATPase concentration was normal after cisplatin treatment. This is contrary to what was expected (Dorup et al, 1988b;Clausen, 1998), and may be caused by prednisolone administered as antiemetic to cisplatin-treated patients, since it reportedly upregulates the skeletal muscle Na,K-ATPase concentration (Thompson et al, 2001). Thus, prednisolone may prevent K depletion in cisplatin treatment from reducing muscle cell K reuptake capacity further.…”

Activities of UDP-glucuronyltransferase, beta-glucuronidase and deiodinase types I and II in hyper- and hypothyroid rats

“…During dissection it was evident that hyperthyroid organs were much more richly innervated by blood vessels than their controls and hypothyroid organs less (data not shown). It is well established from studies in rat and human skeletal muscle that ouabain binding site density reflects the total population of functional Na + /K + pumps (Clausen 1998), which changes proportionally to thyroid status (Kjeldsen et al 1984, 1986, Everts 1996. Table 2 shows that soleus muscle from hyperthyroid rats expressed significantly more ouabain binding sites than their controls, whereas hypothyroid rats expressed fewer binding sites.…”

Na+-K+-ATPase α2-gene and skeletal muscle characteristics in response to long-term overfeeding

“…Therefore a low capacity for fat oxidation in skeletal muscle could be metabolically unfavorable. Na ϩ -K ϩ -ATPase is an essential plasma membrane enzyme catalyzing the transport of Na ϩ and K ϩ across the cell membrane in skeletal muscle (3). Na…”