Mechanisms of Na+-K+ pump regulation in cardiac myocytes during hyposmolar swelling

We have previously demonstrated that the sarcolemmalNa⁺-K⁺pump current(I_p) in cardiacmyocytes is stimulated by cell swelling induced by exposure tohyposmolar solutions. However, the underlying mechanism has not beenexamined. Because cell swelling activates stretch-sensitive ionchannels and intracellular messenger pathways, we examined their rolein mediating I_pstimulation during exposure of rabbit ventricular myocytes to ahyposmolar solution.I_p was measuredby the whole cell patch-clamp technique. Swelling-induced pumpstimulation altered the voltage dependence ofI_p. Pumpstimulation persisted in the absence of extracellularNa⁺ and under conditions designedto minimize changes in intracellular Ca²⁺, excluding an indirectinfluence on I_pmediated via fluxes through stretch-activated channels. Pumpstimulation was protein kinase C independent. The tyrosine kinaseinhibitor tyrphostin A25, the phosphatidylinositol 3-kinase inhibitorLY-294002, and the protein phosphatase-1 and -2A inhibitor okadaic acidabolished I_pstimulation. Our findings suggest that swelling-induced pumpstimulation involves the activation of tyrosine kinase,phosphatidylinositol 3-kinase, and a serine/threonine proteinphosphatase. Activation of this messenger cascade maycause activation by the dephosphorylation of pump units.