[New aspects on the mode of action of cardiac glycosides]

A dissociation of the therapeutic from the toxic effects of cardiac glycosides has repeatedly been described. Whereas it is generally accepted that the toxic effects of cardiac glycosides are based on an inhibition of the Na+-K+-ATPase, the mechanism of action of therapeutic concentrations of cardiac glycosides still remains uncertain. To test the hypothesis, that cardiac glycosides might be transported into a distinct compartment of the myocardium with the Na+-K-ATPase acting as a carrier, the interaction of some inhibitors of this enzyme (digitoxin, dihydroouabain, cassaine, N-ethylmaleimide, p-hydroxy-mercuribenzoate, ethacrynic acid, spironolactone) with ouabain was studied at different levels of cardiac glycoside actions: Myocardial function, cardiac uptake and subcellular distribution and binding to the Na+-K+-ATPase. The following results were obtained: All cardioactive drugs (ethacrynic acid and spironolactone showed no such effects) reduced dose-dependently the inotropic action of ouabain and in high concentrations increased its toxicity. The same drugs inhibited dose-dependently the cardiac uptake of ouabain without affecting the subcellular distribution pattern of ouabain. The binding of ouabain to the Na+-K+-ATPase was influenced in a similar way by these drugs, showing a competitive type of interaction with digitoxin, dihydroouabain and cassaine and a non-competitive mechanism with N-ethylmaleimide and p-hydroxymercuribenzoate. These results support the concept of a cardiac glycoside-ATPase interaction as a basis for the therapeutic action of these drugs. This may be explained either by a direct influence of cardiac glycosides on the ATPase activity and/or by a carrier mediated cardiac glycoside-transport into a distinct compartment of the myocardial cell.