The cardiac glycosides, when used in therapeutic concentrations, increase the strength of contraction of the heart. Toxic concentrations, while continuing to increase inotropy, also lead to cardiac arrhythmias. This study will analyze the role of the sodium pump and of intracellular Na ion activity (Nai) in the therapeutic and toxic effects of cardiotonic steroids in sheep cardiac Purkinje fibers. The proposed research makes use of the electrogenic nature of the Na pump in order to measure its relative activity. By using a two microelectrode voltage clamp technique while simultaneously measuring Nai (using a Na-sensitive intracellular microelectrode) and tension, this study will develop evidence concerning the role of the Na pump in the therapeutic actions of the cardiotonic steroids. The first step will be to characterize the dependence of Na pump rate on extracellular "activator cations" (e.g. T1, K, Rb, Cs, NH4, Li) and on intracellular Na. Using this well defined system, the tension effects of low concentrations of strophanthidin (10 to the minus 9th power M to 10 to the minus 7th power M can be investigated with respect to changes in Na pump activity and Nai. Because of the relationship between the slow inward (calcium) current (Isi) and tension, and because of reports linking low doses of strophanthidin to increases in this current component, Isi will be investigated as well. Experiments will be done to determine whether the increase in Isi results from the direct action of cardiotonic steroids or is mediated by one of the sequelae of cardiotonic steroid action (e.g. an increase of Nai). Finally, it is known that local anesthetic antiarrhythmics such as lidocaine decrease Na entry into heart cells and antagonize the tension effects and arrhythmogenic actions of cardiotonic steroids. For example, it has been demonstrated that lidocaine can reverse the arrhythmogenic "transient inward current" (TI) produced by Na pump blockade. The proposed study will, therefore, examine the role of Nai in the antiarrhythmic action and the negative inotropic effects of lidocaine.