Synergistic interaction between ouabain and 8-methoxy-3,9-dihydroxy coumestan, a non-steroidal synthetic inhibitor of Na+,K+-ATPase
| Autor: | Alcides J. M. da Silva, François Noël, Elisa Suzana Carneiro Pôças, Natália Araújo Touza, Paulo R. R. Costa |
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| Rok vydání: | 2007 |
| Předmět: |
Male
ATPase In Vitro Techniques Pharmacology Kidney General Biochemistry Genetics and Molecular Biology Ouabain chemistry.chemical_compound Coumarins Coumestan medicine Animals Enzyme Inhibitors Rats Wistar General Pharmacology Toxicology and Pharmaceutics Binding site Na+/K+-ATPase IC50 Benzofurans chemistry.chemical_classification Binding Sites biology Glycoside Drug Synergism General Medicine Wedelolactone Rats chemistry biology.protein Sodium-Potassium-Exchanging ATPase medicine.drug |
| Zdroj: | Life Sciences. 81:1199-1204 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2007.08.021 |
| Popis: | The use of combination drugs is very common in therapeutics as in the treatment of infectious diseases, cancer and heart failure but controversies about analysis of these interactions are frequent. The aim of the present work was to characterize the interaction between ouabain and 8-methoxy-3,9-dihydroxy coumestan (LQB93), a non-steroidal synthetic inhibitor of Na+,K+-ATPase, as well as the interaction between ouabain and ouabagenin, two cardiac glycosides sharing the same binding site. Inhibition of rat kidney Na+,K+-ATPase with increasing concentrations of the drugs alone or of mixtures of ouabain:ouabagenin and LQB93:ouabain in a fixed 1:4 ratio was performed. In other experiments, increasing concentrations of LQB93 (or ouabain) in the presence of a fixed concentration of ouabain (or ouabagenin) were used for determining the concentration pairs eliciting 50% inhibition in order to construct isobolograms. The mixture (experimental) curve for the ouabain:ouabagenin combination was superimposed on the additive (theoretical) curve indicating additivity, in accordance with the isobolographic analysis. On the other hand, the empirical curve for LQB93:ouabain (IC50=10.6 microM) was significantly shifted to the left in relation to the theoretical curve (IC50=30.7 microM) indicating synergism, further confirmed by the isobolographic analysis. As a conclusion, we show that the combination of a newly synthesized non-steroidal inhibitor and ouabain have a synergistic effect on Na+,K+-ATPase, further supporting a mechanism of inhibition different from ouabain. Present data also support the use of both the isobolograms and combination curves for the assessment of drug interactions occurring at the same molecular target, a situation poorly investigated. |
| Databáze: | OpenAIRE |
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