Calcium and the mechanism of action of digitalis.

A critical review is made of the mechanism by which digitalis increases the force of contraction of heart muscle. First, it is concluded that the initial step is always an inhibition of the sodium pump, and that the postulated stimulation of the pump by low digitalis concentrations is, possibly, not a real phenomenon. Secondly, the major theories that try to explain the inotropic effect of digitalis are analyzed, and it is tentatively concluded that the effect occurs because Na increases close to the inner side of the plasma membrane, and this decreases Ca efflux through the Na-Ca "exchange" mechanism. An internal Ca store, probably the sarcoplasmic reticulum, that competes with the plasma membrane for Ca, is then able to capture and, subsequently release, a larger fraction of the Ca mobilized during each transient. It is also concluded that the digitalis-induced larger Ca transients can be entirely explained because of a greater Ca "injection" into the cytoplasm during each beat, and not because of changes in resting pCa. A comprehensive model is presented that seems to explain in some detail both the inotropic and the toxic effect of digitalis.