THE PROBLEM OF Na⁺ + K⁺ ADENOSINE TRIPHOSPHATASE AS THE RECEPTOR FOR DIURETIC ACTION OF MERCURIALS AND ETHACRYNIC ACID

¹ Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida

Unless the following inconsistencies are resolved the Na⁺ + K⁺ adenosine triphosphatase (ATPase) cannot be implicated as the receptor for the diuretic action of mercurials and ethacrynic acid. 1) In vitro nondiuretic mercurials, p-chloromercuribenzoate (PCMB) and p-chloromercuriphenylsulfonate (PCMPS), are equal or more potent inhibitors than diuretic mercurials, mercaptomerin and chlormerodrin. After administration to intact dogs both PCMB and chlormerodrin (as measured by radioactivity) are bound equally to the renal membrane fraction, the site of Na⁺ + K⁺ ATPase, in concentrations capable of a substantial inhibition (<50%) in vivo. 2) In vitro the inhibitory effects of mercaptomerin and PCMB are additive, in contrast to their antagonism in vivo. 3) There is no decrease in the renal enzyme activity after an administration of mercaptomerin, PCMB or PCMPS, with a possible slight reduction after chlormerodrin. 4) In dogs pretreated with ethacrynic acid the binding of the drug (as measured by radioactivity) to the membrane fraction is 1000- to 2000-fold less than the binding required for 50% inhibition of the enzyme. The only positive correlations between the inhibition of the Na⁺ + K⁺ ATPase and the diuretic response are: 1) the inhibition by mercaptomerin (in contrast to PCMB) and mercurial diuresis are potentiated by acidosis; 2) neither the inhibition nor the diuresis is affected by pH with ethacrynic acid. Other data are presented which are more difficult to interpret. The sum of these findings challenges the small body of evidence that cardiac glycosides inhibit the renal reabsorption of Na⁺ by a simple inhibition of the Na⁺ + K⁺ ATPase. The summary of various diuretic combinations is: 1) noninhibitors, hydrochlorothiazide, acetazolamide, probenecid and mannitol, do not prevent the natriuretic effect of ouabain; 2) potent inhibitors, PCMB and PCMPS, neither prevent nor abolish the natriuresis induced by ouabain; 3) ouabain produces less than usual natriuresis, or loses effect, in animals pretreated with mercaptomerin, chlormerodrin or ethacrynic acid. In a few experiments mercaptomerin and ethacrynic acid do not increase the excretion of Na⁺ during a large natriuretic response to ouabain. This may suggest that diuretic mercurials and ethacrynic acid act either at the same receptor as ouabain or may interrupt a link within the ouabain-sensitive chain of Na⁺ reabsorption.

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