Cardiac arrhythmias area a major cause of sudden death and morbidity in the US. With the increased survival of patients with coronary artery disease, has come a greater demand for effective treatment of arrhythmias. Disturbances in the behavior of membrane ionic channels, or in the gradients controlling ionic movements of these channels are the ultimate basis of these arrhythmias. My long term objectives are to investigate the cellular mechanisms of cardiac arrhythmias, and their treatment by drugs. To this end, I plan to investigate the mechanism of blockade of Na and K channels by antiarrhythmic drugs in cardiac muscle. Analysis of the molecular mechanism(s) of blockade of ionic channels require measurement of membrane current under voltage clamp with known transmembrane ionic activity gradients. This has been difficult or impossible to achieve using conventional techniques. I shall use the extracellular patch clamp technique to study the properties of individual cardiac Na and K channels and the mechanisms of their interaction with antiarrhythmic drugs. The approach permits the direct measurement of the gating kinetics of channels based on the transition rate constants between their conductance states. Drug dissociation constants can be directly calculated. The technique permits the precise control of intra and extracellular activity gradients. Changes in ionic milieu which may be important factors in arrhythmogenesis can be studied directly. I shall address the following the following questions: 1. Do antiarrhythmic drugs block ionic channels by the random blockade of individual channels or by a reduction in conductance of all the channels. 2. Does the frequency dependent blocking action of antiarrhythmic drugs reside in the voltage dependence of drug dissociation constants, or the stabilization of particular configurations of the channel. 3. What is the comparative efficacy of the commonly used antiarrhythmic drugs for open channel blockade. 4. Do pH and Ca alter the gating kinetics of Na and K channels, and the blocking action of antiarrhythmic drug. 5. What is the simplest model that can account for the blocking action of drugs. These studies should increase our fundamental understanding of individual ionic channels in cardiac muscle, and their mechanisms of interaction with antiarrhythmic drugs.
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