MODELS OF DRUG BINDING TO CARDIAC SODIUM CHANNELS

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The long term objective of this proposal is to develop a quantitative basis for action of antiarrhythmic drugs in cardiac muscle. The increase in number and modes of action (sodium channel, calcium channel blockers) of drugs has created expanded opportunities for pharmacologic management of a number of cardiac arrhythmias. There has been little progress in describing a quantitatively accurate process depicting drug-channel interaction and the associated effect on the cardiac conduction system. The modulated receptor hypothesis for cardiac tissue postulates a variable affinity receptor and interaction between channel gates and drug complexed channels. We have suggested a considerably simpler process based on gated control of the diffusion path between drug pool and channel binding site. An "apparent" variable affinity receptor arises as a natural consequence of this approach. Further, an "apparent" modification of gate kinetics arises naturally. This work will focus on extending this description of channel blocking agents to a propagating system; evaluate the potential effect of blocking agents on current, voltage and conductance relationships in a propagating and voltage clamped setting; and investigate the potential role of blocking agent mediated changes in propagation velocity. We expect our studies of propagated action potentials in the presence of channel blocking agents to illuminate the relationship between ionic currents, voltage and conductance, and thus aid in the design of appropriate experimental protocols focused on minimizing confounding effects.