Comparative ability of digoxin and an aminosugar cardiac glycoside to bind to and inhibit Na +,K +-adenosine triphosphatase : Effect of potassium

Abstract

We compared the abilities of digoxin and aminogalactose digitoxigenin (ASI-222) to bind to, or inhibit, purified dog heart Na +,K +-ATPase in the presence of 1, 10, or 80 mM potassium chloride. Changing the potassium concentration from 1 to 10 mM increased the dose producing 50% inhibition of enzyme activity ( IC 50) by 9- and 2.5-fold for digoxin and ASI-222 respectively. Raising the potassium concentration to 80 mM increased the IC 50 for digoxin 3-fold but did not alter significantly the IC 50 for ASI-222. Equilibrium binding studies showed that this enzyme exhibited a single class of specific binding sites for both digoxin and ASI-222. Raising the potassium concentration did not affect the maximum number of binding sites ( B max) but increased the apparent dissociation constant ( K D ) for digoxin. Potassium differentially affected the affinity and number of binding sites for ASI-222; raising the potassium concentration from 1 to 10 mM did not affect the B max or the K D , but raising it to 80 mM increased both. The effect of i.v. infusion of potassium chloride upon cardiac arrhythmias produced by i.v. infusion of digoxin or ASI-222 in anesthetized dogs was also determined. Infusion of potassium chloride reversed the cardiac arrhythmias due to digoxin to normal rhythm, but not those due to ASI-222. In conclusion, the interaction of digoxin and the polar digitals agent, ASI-222, with dog heart Na +,K +-ATPase was differentially affected by potassium. These agents also produced cardiac arrhythmias, which were differentially affected by potassium.