New developments in the understanding of the actions of the digitalis glycosides.

Abstract In recent years it has become clear that the fundamental action of digitalis in the relief of congestive heart failure is its ability to enhance the contractile state of the ventricle. This positive inotropic effect is a direct action of the drug and is observed in both the failing and normal heart. In patients without a lowered cardiac output, the contractile effect is not translated into an elevation of total blood flow, principally due to the direct arteriolar constrictor action of the drug which increases the resistance to ventricular ejection, and perhaps the constrictor effect on the hepatic veins which results in little change or a decline in venous return to the heart. In contrast, in patients with congestive heart failure, the glycoside produces a marked rise in the reduced cardiac output and thereby allows relaxation of the intense sympathetic-mediated vasocontriction characteristic of the heart failure state; thus, arteriolar and venous dilation due to reflex withdrawal overrides the mild direct vasoconstrictor effect of the drug. From these observations, it is concluded that the digitalis glycosides have important direct and indirect actions on the heart and peripheral circulation, and the overal effects of these agents on the cardiac output and other hemodynamic variables are dependent on the presence or absence of heart failure at the time the drugs are administered. Thus, the glycosides' enhancement of the contractile state of the heart, viewed as a muscle and considered in terms of the mechanics of contraction, is observed as an improvement of the heart examined as a pump only when there is abnormal cardiac performance. Present evidence implies that the basic contractile action of digitalis rests upon its cellular effect of potentiating excitation-contraction coupling. This effect appears to be mediated by glycoside-induced enhancement of the intracytoplasmic concentration of calcium ions around the myofibrils during electrical activation, thereby potentiating contraction. More specifically, it is speculated that digitalis has the ability to alter the configuration of the cell membrane of cardiac muscle, thus increasing calcium and sodium influx during depolarization; these cations then are taken up by sarcoplasmic reticulum which results in the release of microsomal-bound calcium into the myoplasm surrounding the contractile machinery. It is likely that the arrhythmia-provoking properties of digitalis are related to the loss of intracellular potassium and the inhibition of the membrane pump ATPase system required for maintaining intracellular potassium concentrations. This postulation that the inotropic and certain toxic actions of digitalis are mediated by different mechanisms is important clinically, since the two properties of the glycoside can be dissociated by the administration of potassium. The increase in myocardial contractility produced by digitalis requires an increase in myocardial oxygen consumption, as it does for other inotropic agents. In the presence of heart failure, this direct effect on myocardial oxygen consumption may be masked by the drug's favorable indirect effects on certain hemodynamic variables which result in the reduction of total myocardial oxygen requirements. From the above observations, it is apparent that a thorough understanding of the hemodynamic and cellular actions of the glycosides is essential for the proper application of these extraordinarily beneficial drugs in patients.