title: Effect of the digitoxigenin derivative, INCICH-D7, on Na+, K+-ATPase.
abstract: Compound 14beta,17beta-cycloketoester-3beta-OH androstane (INCICH-D7) is a semisynthetic product of a structural modification of the digitoxigenin molecule. INCICH-D7 has a heterocyclic ketoester type fusion between positions C14 and C17 of the steroid nucleus, which confers this molecule stronger electronegativity than that of digitoxigenin. INCICH-D7 retained positive inotropic effect, with a greater safety margin, when compared to digitoxigenin and ouabain. In this study we have examinated the INCICH-D7 effect on Na+, K+-dependent adenosinetriphosphatase (Na+, K+-ATPase) and compared these results with the ones observed with digitoxigenin and ouabain. The inhibitory effect of INCICH-D7 on Na+, K+-ATPase was five times lower (IC50=4 microM) than that of ouabain (IC50=0.8 microM) and 70 times lower than that of digitoxigenin (IC50=0.06 microM). The inhibitory effect of INCICH-D7 and ouabain on the enzyme was irreversible while digitoxigenin's one was reversible in up to an 80%. Our results indicate that inclusion of the heterocycle between positions C14 and C17 in the digitoxigenin molecule lowers significantly the inhibitory effect on Na+, K+-ATPase and renders the interaction between INCICH-D7 and enzyme irreversible under the studied reaction conditions.
authors.affiliation: Instituto Nacional de Cardiología Ignacio Chávez, Departamento de Farmacología, Juan Badiano number 1, Col. Sección XVI, México, D.F., CP 14080, Mexico. margarita0022@yahoo.com
authors.forename: Margarita
authors.initials: M
authors.lastname: Ramirez
authors.forename: Leonardo
authors.initials: L
authors.lastname: Del Valle
authors.forename: Alicia
authors.initials: A
authors.lastname: Sanchez-Mendoza
authors.forename: Fermin Alejandro
authors.initials: FA
authors.lastname: Tenorio
authors.forename: Gabriela
authors.initials: G
authors.lastname: Zarco
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pastelin
mesh_terms: D000818:Animals; D004073:Digitoxigenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006868:Hydrolysis; D007679:Kidney Medulla / Q000201:enzymology; D010042:Ouabain / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C504216:INCICH-D7; D004073:Digitoxigenin; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase