Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Canrenone is the major metabolic product of the synthetic steroids spironolactone and K+-canrenoate, used in antihypertensive therapy. Canrenone can competitively displace [3H]ouabain from Na,K-ATPase [Na+- and K+-activated, Mg2+-dependent adenosine triphosphatase (E.C.3.6.1.3)] and partially inhibit enzymatic activity. These features have led to a hypothesis that competition between canrenone and endogenous digitalis-like materials, suggested to be involved in etiology of essential hypertension, could underly the antihypertensive effect of canrenone. Surprisingly, three derivatives of canrenone (6 beta,7 alpha-,6 beta,7 beta-, and 6 alpha,7 alpha-dihydroxy-6,7-dihydrocanrenone) reportedly occur in normal human and rat urine. This paper characterizes the interactions with partially purified renal Na,K-ATPase of canrenone, the three 6,7-dihydroxylated derivatives, and one epoxide intermediate, synthesized from K+-canrenoate. Canrenone and all the 6,7-substituted derivatives partially inhibited Na,K-ATPase activity (39-45%), with approximately the same apparent affinity, 100-200 microM. Canrenone displaced [3H]ouabain in an apparently competitive fashion (Ki = 100-300 microM) but none of the tested derivatives significantly displaced ouabain even at very high concentrations. The ability to differentiate the ATPase inhibition and [3H]ouabain displacement by modification of the 6,7-double bond indicates that inhibition of ATPase activity does not occur from within the ouabain binding site. We suggest that neither canrenone nor the 6,7-derivatives bind to the ouabain site, but rather interact with it 'allosterically.' Our findings do not support the proposed mechanisms for the antihypertensive action of canrenone.
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PMID:Do canrenone and 6,7-dihydroxylated derivatives compete with ouabain at the same site on Na,K-ATPase? 284 43

Canrenone, a spironolactone metabolite, was tested for its possible effects on (Na+-K+) adenosine triphosphatase (ATPase) activity [Mg++-dependent, (Na+-K+)-activated ATP phosphohydrolase (E.C.3.6.1.3) and ouabain interaction with the enzyme. Canrenone competitively antagonized the binding of [3H]ouabain to (Na+-K+)ATPase and inhibited (Na+-K+)ATPase activity. The multiple inhibition technique was used to demonstrate that canrenone is a partial inhibitor of (Na+-K+)ATPase, mutually exclusive with respect to ouabain. Comparative studies of the effects of ouabain and canrenone on potassium-dependent p-nitrophenylphosphatase activity (E.C.9.6.1.7) and potassium activation of (Na+-K+)ATPase confirmed that ouabain and canrenone interacted with the same receptor site. The finding that canrenone is a partial agonist may explain the results of previous in vivo studies showing that spironolactone and the allied drug to potassium conrenoate have either a positive inotropic action or an antagonistic effect against digitalis toxicity.
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PMID:Canrenone as a partial agonist at the digitalis receptor site of sodium-potassium-activated adenosine triphosphatase. 626 96