THERAPEUTIC AND TOXIC ACTIONS OF DIGITALIS

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Digitalis is commonly used in the treatment of congestive heart failure. However, its clinical usefulness is marred by its toxicity. We will examine how digitalis produces its positive inotropic effect in isolated sheep heart Purkinje fibers. The hypothesis that we will test is that digitalis acts by inhibiting the sodium pump and that the resulting increase in intracellular sodium ion activity (aiNa) is responsible for the increased calcium ion available for contraction. We will examine the requirement of digitalis inotropy for increased aiNa by blocking the accumulation of Na with pharmacological and physiological interventions. This will be accomplished through the use of a two microelectrode voltage clamp protocol in which low holding potential and tetrodotoxin will be used to limit Na influx. Both twitch tension and aiNa will also be monitored, the latter with a Na-sensitive intracellular microelectrode. In this way we will be able to determine if a rise in aiNa is in fact essential to the positive inotropic action of cardiac steroids. Inhibition of Na, K countertransport by digitalis is also known to be responsible for the occurrence of digitalis-induced voltage, current and tension oscillations. These oscillations have received much attention recently because they may underlie the arrhythmias associated with digitalis intoxication. We will use voltage clamp methods and ion sensitive intracellular microelectrodes to measure changes in Na and Ca activities associated with the occurrence of the oscillations. In this way we will quantify changes in ionic composition which 1) result from Na pump inhibition and 2) in turn may influence the mechanical and electrical expression of digitalis toxicity. We will also examine effects of holding potential on ionic composition and the digitalis oscillations because of the depolarizing effect of digitalis and of the effect of transmembrane potential on intracellular ions. This study will provide new information about 1) how digitalis produces its therapeutic action; 2) whether or not the therapeutic and toxic actions of digitalis can be separated so that safer agents can be manufactured; 3) how digitalis intoxication affects intracellular ionic composition; 4) how changes in intracellular ions and membrane potential influence the expression of glycoside toxicity (through oscillations and arrhythmias); and 5) how Na and Ca influence the force of contraction of the heartbeat in general.