AGONIST EFFECT OF ANTIARRHYTHMIC DRUGS

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In preliminary studies, we have identified an ~agonist~ action of prototypical ion channel blockers. It is the overall goal of studies in this Project to further determine mechanisms underlying this effect, defined here as a modification of channel gating that leads to a drug-induced increase in current in the voltage range of the plateau phase of the cardiac action potential. Our studies to date have demonstrated such an effect on Kv1.5-mediated currents by quinidine, by the local anesthetic bupivacaine, and by docosahexaenioc acid (the main polyunsaturated fatty acid in fish oils) and on HERG-mediated currents by quinidine. The experiments proposed will use these agents to study agonist effects on Kv1.5, Herge, and Kv4.3, genes whose products are major alpha-subunits underlying human delayed rectifier and transient outward currents. Specific Aim 1 will use biophysical approaches to test the hypothesis that a specific binding site exits for the agonist effect, and will analyze these results in terms of advanced gating models. Specific Aim 2 will identify physicochemical properties of individual drugs that determine the agonist action; this work may lead to identification or synthesis of ~purer~ agonist. The goal of Specific Aim 3 is to identify the molecular locus of a binding site for the agonist effect; the working hypothesis is that an interaction with the voltage sensor (S4) or its ~canaliculus~ is responsible. Reduced ion current is increasingly recognized as a potential contributor to arrhythmias, so further understanding of this agonist effect should have important implications for new drug development. More generally, it is well-recognized that patients vary widely in their responses to antiarrhythmic drugs; the coexistence of antagonist and heretofore- unrecognized agonist effect in single molecules has important implications for understanding this variability.