Selective inhibition of the cellular sodium pump by emicymarin and 14ss anhydroxy bufadienolides

Hilton, Philip, McKinnon, William, Gravett, Edward, Peron, Jean-Marie, Frampton, Christopher M, Nicholls, M Gary and Lord, Gwyn (2010) Selective inhibition of the cellular sodium pump by emicymarin and 14ss anhydroxy bufadienolides. Steroids, 75(13-14), pp. 1137-1145. ISSN (print) 0039-128X

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Abstract

Partial inhibition of the sodium pump (Na/K ATPase) by a circulating inhibitor is known to occur in humans. The objectives of this study were to determine the effects of novel bufadienolides lacking an oxygen at C14 on sodium pumps in human erythrocytes and leucocytes, dog kidney and pig brain and to document the importance of the stereochemistry at C17 on the ability to inhibit these sodium pumps. 14alpha bufadienolides were weak inhibitors of all preparations studied. 3ss-OH,5ss,14ss bufadienolide produced near-total inhibition of dog kidney and pig brain Na/K ATPase. Over the same concentration range, it maximally inhibited the sodium pump of erythrocytes by 70% and leucocytes by 47%. The inhibition profile induced in the leucocyte sodium pump deviated significantly from the simple sigmoidal relationship present in the other preparations over the 3x10-5 to 1x10-7mol/l concentration range. Allo-emicymarin (17alpha) was confirmed to be a weak inhibitor of the sodium pump/ATPase compared with emicymarin (17ss) but both were weaker inhibitors of the leucocyte sodium pump than that of the other preparations. Molecules with the C14 in the ss configuration are more efficacious than in the alpha configuration. In the case of emicymarin, the attachment of the furone at C17 in the alpha configuration results in substantially weaker inhibitory activity than in the beta configuration, seen in most cardenolides and bufadienolides. Unlike ouabain and bufalin that show no specificity of action in these preparations, 3ss- OH,5ss,14ss bufadienolide selectively inhibits the activity of at least one low-prevalence subset of the leucocyte Na/K ATPase.

Item Type: Article
Research Area: Chemistry
Pharmacy
Biological sciences
Faculty, School or Research Centre: Faculty of Science (until 2011) > School of Pharmacy and Chemistry
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Depositing User: Automatic Import Agent
Date Deposited: 13 Aug 2010 15:03
Last Modified: 04 Feb 2011 16:22
URI: http://eprints.kingston.ac.uk/id/eprint/15741

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