On the differences between ouabain and digitalis glycosides.

Digoxin and digitoxin are widely used in the treatment of heart diseases. The exact mechanism of action of these drugs has remained an enigma. Ouabain has become the standard tool to investigate the mode of action of cardiotonic steroids, and results with ouabain are regarded as generally valid for all cardiac glycosides. However, there are marked differences between the effects of ouabain and digitalis glycosides. Ouabain has a different therapeutic profile from digitalis derivatives. Unlike digitalis glycosides, ouabain has a fast onset of action and stimulates myocardial metabolism. The inotropic effect of cardiotonic steroids is not related to inhibition of the Na-K-ATPase. Ouabain and digitalis derivatives develop their effects in different cellular spaces. Digitalis glycosides increase the intracellular calcium concentration by entering the cell interior and acting on the ryanodine receptors and by forming transmembrane calcium channels. Ouabain, by activation of the Na-K-ATPase from the extracellular side, triggers release of calcium from intracellular stores via signal transduction pathways and activates myocardial metabolism. These data no longer support the concept that all cardiotonic steroids exhibit their therapeutic effects by partial inhibition of the ion-pumping function of the Na-K-ATPase. Hence, it is suggested that this deeply rooted dogma be revised.

Ouabain--the key to cardioprotection?

Based on a wealth of mechanistic evidence supported by the fact that ouabain mimics the spleen-liver effect in this article, the hypothesis is established that the endogenous hormone ouabain not only mimics the effects of ischemic preconditioning but also may be an ideal drug for the prevention of ischemic diseases. Moreover, it is argued that the spleen-liver effect may represent a general protective mechanism for the protection of organisms against oxygen deficiency. Investigating the spleen-liver mechanism offers a new approach to decipher the secrets of ischemic conditioning. Preconditioning represents a basic mechanism to protect a wide variety of cells against stressful stimuli such as ischemia. The ability to undergo preconditioning is almost ubiquitous in tissues and is highly conserved across species. Reinvestigation of the "spleen-liver mechanism" will allow the study of metabolic inhibitors and hormone mimics that all could help to transform ischemic preconditioning into a cure of the epidemic ischemic heart disease. Ouabain mimics the effects of the spleen factor. Cardioprotection induced by ouabain is due to the activation of pathways that are also activated in ischemic preconditioning. Just like ischemic preconditioning, ouabain activates the reperfusion injury salvage kinase pathway. Activation of nuclear factor kappa B and other transcription factors contribute to the long lasting effects of ouabain. The endogenous hormone ouabain just like preconditioning offers multiorgan protection based on innate mechanisms, which warrants clinical investigation. Clinical studies with ouabain that correspond to current standards are warranted.