Na, K-ATPase in the myocardial cell membrane is essential for the generation and maintenance of transmembrane electro-chemical gradients and hence for the maintenance of excitability of cardiac cells. Cardiac glycosides inhibit this enzyme system and also increase the force of cardiac contraction. These two events seem to be related: the enzyme inhibition by cardiac glycosides causes an enhanced intracellular sodium transient associated with membrane excitation, resulting in an enhanced calcium transient and increased force of contraction. The objective of this project is to demonstrate the causal relationship between the inhibition of cardiac Na, K-ATPase and the inotropic action of the cardiac glycosides. This will be achieved by studying the quantitative relationship between the enzyme inhibition by various inhibitors including cardiac glycosides, and the changes in developed tension during the development and dissipation of the drug action. Other hypotheses, i.e., the binding of the glycosides to Na, K-ATPase represents the first step of the transport of these agents to unidentified intracellular site of action, or the binding of the drug to Na, K-ATPase provides additional calcium pool within the cell membrane, will also be tested. Further, the consequences of sodium pump inhibition which lead to the positive inotropic and/or toxic effects will be studied. Influences of modifiers of the action of cardiac glycosides on Na, K-ATPase will be compared with those on the inotropic and/or toxic actions. Finally, the differences in the sequence of biochemical events which link Na, K-ATPase inhibition to inotropic or toxic effects, respectively, will be explored.