NA+/K+-ATPase and inhibitors (Digoxin)
The beneficial properties of digital extracts, recognized for several centuries, have been confirmed in 1785 by the English physician Whitering. One of their active compounds, digitalin, was obtained by the French pharmacist Nativelle one century later. The cardiac inotropic and bradycardiac effects of digitalin were recognized but their mechanism of action, the inhibition of Na + /K + -ATPase pump, was discovered only recently. The most frequently cardiac glycoside used today is digoxin.
Na+/K+-ATPase ATPase pump, like H+/K+-ATPase and Ca+/K+-ATPase, is an enzyme which plays the role of pump. It ensures the transmembrane transfer of the cations Na+ and K+. Na+/K+-ATPase is located in the cytoplasmic membranes. It consists of two alpha catalytic subunits and of two beta subunits. Na+/K+-ATPase uses the energy released by the hydrolysis of the ATP in the presence of magnesium to ensure the transport of three Na+ ions outside the cell and of two K+ ions inside.
Na+/K+-ATPase has three main functions:
Cardiac glycosides, digoxin, digitoxin also called digitalin, and ouabain, are the principal inhibitors of Na+/K+-ATPase. They bind to the extracellular part of enzyme i.e. that binds potassium, when it is in a phosphorylated state, to transfer potassium inside the cell. Extracellular potassium which induces the dephosphorylation of the alpha subunit reduces the effects of cardiac glycosides.
Cardiac glycosides inhibit Na+/K+-ATPase of the myocardium, cardiac conducting tissue, smooth vascular muscles and some other tissues like erythrocytes. They have little effect on the Na + /K + -ATPase of skeletal muscles.
Consequences of the inhibition of Na+/K+-ATPase by digoxin:
increase of intracellular sodium which is exchanged for calcium
The inhibition of Na+/K+-ATPase induces a rise in sodium concentration inside cells. This sodium increase induces in its turn an increase in the intracellular calcium concentration, via the sodium-calcium exchanger. The sodium-calcium exchanger is particularly active in myocardium and in smooth vascular muscles.
The rise in intracellular calcium increases the force of contraction of the heart and the contracture of smooth vascular muscles.
The inhibition of Na+/K+-ATPase reduces cellular polarization (depolarizing effect).