Electrophysiological studies are planned to advance our understanding of antiarrhythmic drug action and help develop strategies for rational drug design. The modification of Class I drug action (sodium channel blockers) by membrane potential and pH, both conditions likely to be altered in diseased myocardium, will be examined. A quantitative model, developed in this laboratory, that gives rate limiting roles to proton-exchange kinetics for channel-bound drug will be tested in isolated myocyte and voltage-clamped skeletal muscle preparations. Competing receptor models (modulated receptor and guarded receptor) will be compared for their ability to explain the observed pH- and voltage-dependence of drug interactions with muscle sodium channels. Structure/activity relations regarding how drugs differ in their sensitivity to these manipulations will be developed, and molecular mechanisms, in terms of the receptor models, should be revealed. Finally, ionic mechanisms responsible for the regenerative repolarization of ventricular action potentials will be studied, especially during exposure to Class III antiarrhythmics.
