DRUG EFFECTS ON THE NA-TENSION RELATIONSHIP IN HEART

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The Na-Ca equilibrium exchange process is responsible for the extrusion of Ca1 from cardiac cells and is therefore a critical regulatory process in determining the amount of Ca1 available for contraction. We will examine the effects of agents which alter Na1 activity (a-Na-1 on the relation between a-Na-1 (as measured directly using Na-sensitive microelectrodes, Na-ISE) and tension. We will study the effects of tetrodotoxin which blocks Na influx through Na channels, cardiac glycosides which prevent Na efflux via the Na,K pump and several agents which block Na channel inactivation such as veratridine. The purpose for studying these different drugs is to examine the nature of the Na-tension relation under a variety of conditions of increasing a-Na-1. We will also use Ca-1SE in order to more fully characterize the Na-Ca-tension relationships which so strongly influence the contractile state of the heart. These experiments will combine the techniques of isolated dog ventricular cells under voltage clamp control with measurements of a-Na-1 and a-Ca-1 obtained directly with ISE while changes in cell length are monitored. Most of our knowledge of Na-Ca exchange is derived from Purkinje fibers but the present study will directly examine these physiological characteristics in myocardial cells. This study will quantify the Na-Ca-tension relationships which are critical to our understanding of physiological factors that determine excitation-contraction coupling in the heart and of the pharmacological influences on contraction strength. Thus these experiments will not only help us understand some of the physiological processes determining contractile force that may be adversely affected in disease states like heart failure and cardiomyopathy, but will also help us to devise a more rational approach in the development of new positive inotropic agents for the treatment of these diseases.