Muscle contractions induce cellular potassium (K+) efflux which may contribute to impaired muscle cell membrane excitability and fatigue. The magnitude of K+ changes are dependent on the size of contracting muscle mass, duration and intensity of exercise, and health and fitness status of participants. Activation of the sarcolemmal and t-tubular bound sodium-potassium adenosine 5’ triphosphatase enzyme (Na+,K+ATPase, NKA) mediates muscle cell K+ and Na+ active exchange, and is instrumental in the maintenance of muscle cellular and plasma K+ homeostasis during exercise. Therefore modulations of NKA function might enhance or impair exercise induced K+ disturbances, and theoretically can have a profound effect on muscle excitability and exercise performance. This thesis examined the effects of two interventions designed to induce acute or short term upregulation and downregulation of NKA activity on K+ homeostasis and exercise performance in healthy humans. Study 1 investigated the effects of metabolically induced alkalosis on plasma K+ regulation during submaximal finger flexion (small muscle mass) contractions and fatigue in healthy humans. Study 2 investigated the effects of a clinically relevant dose of digoxin administration on K+ regulation, during intermittent supramaximal finger flexion contractions (small muscle mass) and fatigue in healthy humans. Study 3 investigated the effects of digoxin on K+ regulation during progressive increasing intensity submaximal leg cycling exercise (large muscle mass) and fatigue in the same healthy participants as in study 2. A secondary focus of this thesis was to examine the ionic, metabolic and acid-base disturbances during small and large muscle mass exercise and in recovery. This included the regulatory role of NKA in active (study 1 and 2) and inactive tissue (study 3), during small (study 1 and 2) and large (study 3) muscle mass exercise.