STIMULATION OF NA-PUMP ACTIVITY IN SKELETAL-MUSCLE BY METHYLXANTHINES- EVIDENCE AND PROPOSED MECHANISMS(, K+)

Evidence is presented to support the hypothesis that submillimolar con centrations of methylxanthines stimulate Na+, K+-ATPase activity in sk eletal muscle. Administration of methylxanthines to skeletal muscle re sults in plasma membrane hyperpolarization and increased rates of K+ u ptake and Na+ efflux. These effects are both dose- and time-dependent and inhibited by blockers of the Na+, K+ ATPase. The mechanisms for st imulation of Na+, K+-ATPase activity and the signal transduction pathw ays are not known. The methylxanthine concentrations required for stim ulation of Na+, K+-ATPase activity are less than those required to cau se a 50% inhibition of phosphodiesterase activity. and therefore incre ases in cyclic AMP due to inhibition of the enzyme are not involved. P ossible mechanisms by which methylxanthines may increase Na+, K+-ATPas e activity include: (1) a role for increased intracellular [Ca2+]; (2) Ca2+ or adenosine-receptor-mediated increases in intracellular cyclic AMP: and (3) a direct action of methylxanthines on the Na+, K+ ATPase .