Abstract
The signaling function of the Na/K-ATPase has been established for 20 years and is widely accepted in the field, with many excellent reports and reviews not cited here. Even though there is debate about the underlying mechanism, the signaling function is unquestioned. This short review looks back at the evolution of Na/K-ATPase signaling, from stimulation by cardiotonic steroids (also known as digitalis-like substances) as specific ligands to stimulation by reactive oxygen species (ROS) in general. The interplay of cardiotonic steroids and ROS in Na/K-ATPase signaling forms a positive-feedback oxidant amplification loop that has been implicated in some pathophysiological conditions.