Cardiac arrhythmias are a major cause of death and morbidity in the U.S. Despite their proarrhythmic potential, drug remains the mainstay of treatment. The sodium channel-blocking drugs are the principal agents in clinical use. Some of these agents or related structures are also effective anticonvulsants. This research program describes my continuing efforts to understand the cellular basis of arrhythmias and the mechanisms by which they are treated by drugs. The primary focus of the proposed studies is the voltage-gated sodium channel. This channel sustains conduction in most regions of the heart and central nervous system. It also plays a role in the control of action potential duration, pacemaker activity and excitation-contraction coupling. Recently, a complex picture of sodium channel gating is emerging in which the channel switches between various modes of gating with high or low opening probabilities or early and late opening latencies. A general proposition of the mechanism of action of Na-channel activators and blockers is that they stabilize various inherent gating modes. A clear understanding of the gating mode and conductance of channel provide a basis for the study of the electropharmacology of antiarrhythmic, anticonvulsant and inotropic agents. I shall employ the extracellular patch clamp technique to study the sodium channel in native membranes and cloned channels expressed in frog oocyte. The proposal tests three hypotheses: l. The late background sodium current is a major source of inward current at threshold potentials in latent and true pacemakers and is a target for local anesthetic-class antiarrhythmic drugs. 2. Sodium channel """"""""activators"""""""" shift the equilibrium of gating to inherent modes with increased opening probability rather than inducing new gating mode. The shift is effected by binding close to the channel pore. 3. Open Na-channel blockers interact with binding sites in the channel pore. However, interaction with other sites are critical to their overall blocking action. The proposed studies should provide greater insight into the complexities of Na-channel gating. They should provide information at a fundamental level on the mechanism by which channel gating and conductance can be modulated for a therapeutic advantage.
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