Several new compounds that concomitantly increase cardiac action potential duration and myocardial inotropy (e.g. OPC-8212, DPI 201-106, and d-sotalol) have been identified. Although the manner by which these compounds produce their cardiac effects is not well understood, the mechanism(s) responsible are clearly different from those responsible for the effects produced by cardiac glycosides. The purpose, therefore, of this project is to clarify the actions of these new compounds on cardiac ventricular muscle and specialized ventricular conducting tissue electromechanical activity and membrane currents; and, to access the relative importance of each of several possible mechanisms of action. The effects on cardiac action potential duration and developed force produced by these new compounds are similar to those produced by tetraethylammonium (TEA), which is known to reduce outward membrane potassium currents, and by veratridine and ATX II, which have been demonstrated to increase the time during which an inward, tetrodotoxin-sensitive, sodium current occurs during the action potential. These similarities suggest that the new compounds may also lengthen cardiac action potential duration by either reducing outward potassium currents or increasing the duration and magnitude of the inward sodium current. Lengthening action potential duration by either mechanism would be expected to increase intracellular sodium ion activity which, in turn, would be expected to increase intracellular free calcium and force development by affecting sodium-calcium exchange. In addition, it has been suggested that one of the new compounds (i.e. OPC-8212) is a phosphodiesterase inhibitor; and, that therefore, some of the electromechanical effects of this compound may be explained by phosphorylation of cardiac calcium channels and an increase in the magnitude of the inward calcium current. The studies will be performed on isolated rabbit Purkinje strands and rabbit ventricular trabeculae using ion-selective and conventional microelectrode techniques. Additional studies will be performed on enzymatically isolated rabbit Purkinje fiber and ventricular muscle myocytes using patch-clamp technqiues to record whole-cell and single-channel currents. The information to be obtained from these studies will help to clarify the ionic mechanisms responsible for the direct cardiac effects of each of the new compounds. The studies will also provide information that will help clarify the underlying differences in the ionic mechanisms responsible for genesis of the cardiac action potential in ventricular muscle and Purkinje fibers. Of greater importance, however, this study will provide useful information on novel and exciting mechanisms by which cardiac contractility may be pharmacologically increased while providing class III antiarrhythmic activity.
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