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Inhibition of sodium- and potassium-dependent adenosine triphosphatase by ethacrynic acid: two modes of action.

S. Banerjee,V. Khanna,A. K. Sen

Published 1970 in Molecular Pharmacology

ABSTRACT

Ethacrynic acid inhibited sodium- and potassim-dependent adenosine triphosphatase (ATP phosphohydrolase, EC 3.6.1.3) by affecting two different steps of enzyme turnover. First, ethacrynic acid blocked phosphorylation of (Na + + K + )-ATPase with insignificant effect upon the dephosphorylation step when the Na + :K + ratio was 10. It also prevented the ADP-ATP exchange reaction. The reduction in specific activity of the enzyme by ethacrynic acid was closely correlated with the degree of inhibition of phosphorylation and ADP-ATP exchange. Second, ethacrynic acid stabilized the spontaneous disappearance of the phosphorylated intermediate and slightly decreased the apparent affinity for K + . The rate of decay of the phosphorylated intermediate in the presence of ADP was not significantly affected by ethacrynic acid treatment. The decrease in apparent affinity for K + could not be observed in an assay medium with an Na + :K + ratio of 4. When the concentrations of Na + and K + were changed to those found in extracellular fluid, ethacrynic acid-treated enzyme showed a 20-30% decrease in specific activity as compared to the usual assay system. The inhibition of phosphorylation by ethacrynic acid appears to be of significance for inhibition of enzyme activity in vitro , while the stabilization of the phosphorylated intermediate may be involved in drug-induced diuresis.

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