Effects of digitalis on myocardial ionic exchange.

SUMMARY Prior to consideration of the effects of digitalis compounds on ionic exchange the basic mechanisms of active Na+ and K+ transport are discussed. It is generally accepted that digitalis is a specific inhibitor of the Na+-K+ activated ATPase located primarily in the sarcolemmal membrane. Present evidence supports the concept that positive inotropic effects of digitalis are not seen unless evidence of inhibition of the enzyme and, therefore, of the "Na pump" leads to a small increase of intracellular Na+. This leads to augmented activity of a_Na+ transport system which is coupled, not to K+, but to Ca+ +. Evidence for the existence of Na +-Ca + + coupling at excitable membranes is accumulating, and this is reviewed. The possibility that administration of digitalis, through its inhibition of the Na +-K + coupled system produces an increase in Na +-Ca + + coupled transport and thereby an increase of influx of Ca + + to the myofilaments is discussed and is presented as a possible basis for the mechanism of digitalis actionl. The toxic electrophysiologic effects of digitalis are discussed in terms of the effects on K + exchange induced by the drug. Active transport Sarcolemmal ATPase Words: Sodium Cardiac Potassium contractility Calcium exchange Glycoside toxicity F ORTY YEARS ago Calhoun and Harrison1 studied the effect of administration of a digitalis preparation on the potassium content of dog heart. They remarked, "At present time we are not in a position to understand the significance of the fact that even in therapeutic doses there seems to be a slight tendency for digitalis to diminish the potassium content of the heart muscle. The close relation of calcium to digitalis action is well known. .. and it is conceivable that digitalis may act in 180 such a way as to readjust the ionic balance, even at the expense of loss of base from the muscle. . ." The suggestion that digitalis might alter ionic balance was made a quarter of a century before the first definitions of active sodium transport2 and the first outlines of the excitation-contraction coupling sequence in muscle were developed.3 As more has been learned of the complexities of ionic transport and exchange and their relationship to myocardial tension development over the past decade, Calhoun's and Harrison's concept has gained support. The information which forrns the foundation of present ideas of digitalis action comes from the application of diverse technics …