Influence of extracellular K+ concentration on the time-course of Na+/K+-ATPase inhibition by cardiac glycosides with fast and low binding kinetics.

ABSTRACT

The magnitude of the K+ antagonism of cardiac glycoside binding to Na+/K+-ATPase prepared from porcine heart, was estimated from the enzyme activities determined in the presence of different concentrations of K+ ([K+]), ouabain, and alpha-methyl-digitoxigenin-glucoside, the latter showing a 30 fold greater dissociation rate than ouabain. An increase of [K+] (3-20 mmol/l) prolonged the half-lives of Na+/K+-ATPase inhibition and caused a rightward shift of the cardiac glycoside's dose-response curves by the same factor, almost maximal (4 fold) at 14 mmol/l K+. These data could be verified from the cardiac glycoside-elevated intravesicular Na+ concentrations of rat brain vesicles. These concentrations declined rapidly in brain vesicles treated with alpha-methyl-digitoxigenin-glucoside but not with ouabain after K+ was increased from 3.5 to 14 mM. The results suggest that the magnitude of the K+ antagonism under physiological conditions is only limited by the lifespan of the cardiac glycoside-binding E2P enzyme conformation reduced by K+.