Inhibitory effect of combinations of digoxin and endogenous cardiotonic steroids on Na+/K+-ATPase activity in human kidney membrane preparation.
OBJECTIVE
Cardiac glycosides have been extensively used in the treatment of congestive heart failure for more than 200 years. Recently, cardenolides and bufadienolides were isolated from mammalian tissue and are considered as a new class of steroidal hormones. The aim of the present work was to characterize the interaction between the most clinical used cardiac glycoside digoxin and the cardiac glycosides known to exist endogenously, i.e., ouabain, marinobufagin and telocinobufagin, on human kidney Na(+)/K(+)-ATPase.


METHODS
Inhibition of Na(+)/K(+)-ATPase activity from crude membrane preparations of human kidney was performed using increasing concentrations of the drugs alone or mixtures of ouabain:digoxin, telocinobufagin:digoxin and marinobufagin:digoxin in a fixed ratio 1:4, 2:3 and 3:2, respectively. The colorimetric method of Fiske and Subbarow was used to measure the inorganic phosphate released.


RESULTS
Analyses of inhibition curves showed that the experimental curves for all combinations were superimposed on the theoretical additive curves indicating that an additive effect occurs among distinct cardenolides and bufadienolides combinations on the human α1β1 Na(+)/K(+)-ATPase protomer.


CONCLUSIONS
Considering the extensive use of digoxin in the treatment of heart failure and the recent findings that endogenous cardiac glycosides may have altered levels in many diseases, including heart failure, the demonstration of additive effect between cardiac glycosides can help in the understanding of recent clinical observations, including that lower than usual doses of cardiac glycosides are necessary for decreasing mortality in these patients.
Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Natália Araújo
NA
Touza
Elisa Suzana Carneiro
ES
Pôças
Luis Eduardo M
LE
Quintas
Geraldino
G
Cunha-Filho
Maria Lucília
ML
Santos
François
F
Noël
D002018:Bufanolides / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004077:Digoxin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D002018:Bufanolides; D002301:Cardiac Glycosides; D007527:Isoenzymes; C093896:marinobufagenin; C009391:telocinobufagin; D010042:Ouabain; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase