The long term objectives of this application is the investigation of the mechanism by which cardiac steroids modify the electrical and mechancial events of the cardiac tissues.
The specific aims i nclude (1) an evaluation of the mechansisms by which cardiac steroids increase cellualr sodium; (2) the role of cellular sodium level in force development; (3) the relationship between intracellular sodium and the oscillatory potential; (4) the mechanism of abolition of the oscillatory potential; (5) the relative importance of sodium and calcium in cardiac steroid inotropy; (6) the mechanism of the reversal of calcium overload; (7) the analysis of the action of cardiac steroid in the sinus node (8) the mode of action of therapeutic interventions. The experiments will be conducted in isolated perfused tissues. The transmembrane potentials will be recorded with a microelectrode technique together with the twitch. The intracellular sodium activity will be measured with a Na-selective microelectrode. Voltage clamp method will involve the use of two microelectordes in short sigments of Purkinje fibers. The tissues to be investigated include ventricular Purkinje fibers, atrial and ventricular muscle fibers, and the sinus node. The experiments will involve changes in external ionic environment, selective blockage of cardiac currents, changes in transmembrane fluxes of sodium and calcium and the analysis of the dependance of some phenomena on voltage. Both low (""""""""therapeutic"""""""") and high (toxic) concentrations of cardiac glycosides will be used in an effort to determine whether the mechanism of the inotropic effect is the same. The changes in electrical activity, mechanical activity and aiNa will be correlated. The different techniques should permit the identification of the factors of importance in the positive inotropic effect of cardiac steroids and in the electrical and mechanical toxicity induced by high concentrations.
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