ELECTROPHYSIOLOGIC RESPONSES TO ION CHANNEL BLOCKADE

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This renewal request is for continued support of research focusing on the interaction between ion channel blocking agents and cardiac excitable membrane and how this interaction modifies electrical communication between cells. With a biophysically accurate model, we believe that insights into the mechanism of channel blockade can be used to improve control of electrical events in the heart. Moreover, these results can aid in classifying drugs as to their electrophysiological effects. To this end, this work focuses on continued development of a quantitatively accurate model of drug-channel interactions and incorporation of the resulting description into standard models of cardiac action potentials in order to predict the effect of channel blockade on observable extracellular electrical events. Recent reports from the CAST investigators indicate an increased incidence of sudden death in patients treated with flecainide and encainide. Both these drugs are slowly unbinding use-dependent sodium channel antagonists. Computer simulations suggest that use-dependent sodium channel blockade promotes unidirectional block and reentrant arrhythmias initiated by premature stimulation. Moreover, mixtures of a rapidly unbinding drug (e.g. lidocaine) with a slowly unbinding drug can reverse this proarrhythmic potential. Preliminary in vitro studies confirm that slowly unbinding use-dependent sodium channel antagonists prolong the range of delays of premature stimuli that can initiate reentrant arrhythmias. Consequently these studies have direct applicability to the management of complex arrhythmias and the models provide a way to integrate ion channel blockade at the cellular level with tissue responses to premature stimulation. Our objective for the next 5 years is to continue the detailed development of a quantitatively accurate physical model of ion channel blockade, to extend the model to describe use-dependent potassium channel blockade (delayed rectifier and transient outward currents), and to explore both the antiarrhythmic and proarrhythmic potential in in vitro studies and in computer models of 1 and 2 dimensional arrays of coupled cells. Voltage clamp studies of sodium, delayed rectifier and L type calcium channel blockade will be used to estimate kinetic rates of binding and unbinding. Studies of responses to premature stimulation in isolated rabbit left atria will be used to explore anti- and proarrhythmic potential. A major focus will be to couple our understanding of a drug's cellular behavior with observations of multicellular responses to premature stimulation and how these correlations relate to current interests in pharmacologic management of cardiac arrhythmias.