This renewal request is for continued support of research focusing on the macroscopic interaction between ion channel blocking agents and excitable membranes (cardiac and nerve) 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 (and nervous system). 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 and nerve action potentials in order to predict the effect of channel blockade on observable electrical events. Our work during the current 3 year period has focused on validating our original model of sodium channel blockade. A primary goal was to develop a procedure for estimating equilibrium dissociation constants from nonequilibrium data derived from pulse train membrane excitation. The resulting methodology has been partially validated with several sodium channel blocking agents and found also to accurately describe potassium and calcium channel blockade. Our objective for the next 5 years is to continue the detailed development of a quantitatively accurate physical model of ion channel blockage, to couple the blockade model to models of membrane and extracellular action potentials, to extend the model to multiple drugs competing for the same binding site, and to extend to the case of a single drug binding to different channel types. This last goal has become critical as evidence for drugs blocking different channel types (Na+, K+, and Ca++) has become available. Major attention will be directed towards translating the understanding of events at the cellular level to clinical strategies for arrhythmia management.
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