The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase

Abstract

The Na,K-ATPase (or Na pump) is an integral membrane protein that transports Na+ and K+ across the plasma membrane of almost all animal cells and couples this work to the hydrolysis of the terminal phosphate bond of ATP (1). A significant fraction (up to ≈30%) of the ATP generated by cell metabolism is dedicated to this active transport process. The electrical gradient created by the Na pump is essential for the excitable activity of muscle and nerve tissue, and the inwardly directed Na gradient maintained by the Na pump is used in most cells and organs to drive the uptake and accumulation of a wide range of essential nutrients and cellular substrates and to reduce cell calcium and proton concentrations. The Na,K-ATPase also serves as the unique binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin. Plant extracts containing cardiac glycosides have been used therapeutically since the 18th century. The cardiac glycoside site is the pharmacological target for digoxin, which is currently used widely in the treatment of congestive heart failure. However, the strong evolutionary conservation of this binding site among almost all species has suggested that important physiological functions may involve recognition of this site by endogenous agents. The work of Dostanic-Larson et al. in this issue of PNAS (2) demonstrates that the cardiac glycoside binding site of Na,K-ATPase plays an important physiological role in blood pressure regulation. It is reported that ACTH-induced hypertension is abolished when the interaction of cardiac glycosides with the Na,K-ATPase is …