CLINICAL AND THERAPEUTIC SIGNIFICANCE OF THE NA+,K+ PUMP

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 tar get for acute and long-term regulation, as well as for therapeutic int ervention. Acute stimulation of the Na+,K+-pump in skeletal muscle by insulin, catecholamines, beta(2)-agonists or theophylline increases th e intracellular uptake of K+ and accounts for the hypokalaemia elicite d by these agents. Conversely, digitalis intoxication elicits hyperkal aemia via acute inhibition of the Na+,K+-pump. 2. Simple and accurate methods have been developed for the quantification of the total concen tration of Naf,Kf-pumps in small (0.5-5 mg) fresh or frozen biopsies o f human skeletal muscle, myocardium or other tissues. This has allowed the identification of several long-term regulatory changes in the con centration of this transport system in human tissues. In skeletal musc le, upregulation is induced by training, thyroid hormones or glucocort icoids. Down-regulation is seen in hypothyroidism, cardiac insufficien cy, myotonic dystrophy, McArdle disease, K+ deficiency and after muscl e inactivity. 3. Since the skeletal muscles contain one of the major p ools of Na+,K+-pumps, these changes are important for the ability to c ounterregulate the hyperkalaemia elicited by exercise or the ingestion of K+. Moreover, down regulation or inhibition of the Na+,K+-pumps in skeletal muscle interferes with contractile performance. Since digita lis glycosides bind to the Na+, K+-pump, the muscles constitute a larg e distribution volume for these agents and are therefore an important determinant for their plasma level. 4. In cardiac insufficiency, the d ecrease in the concentration of Na+,K+-pumps in the myocardium is over a wide range correlated to the concomitant reduction in ejection frac tion. The regulatory and pathophysiological changes in the activity an d concentration of Na+,K+-pumps are important for the contractile func tion of skeletal muscle and heart as well as for K+ homoeostasis and t he response to digitalization.