OPEN NA- MULTIPLE REST STATES REVEALED BY CHANNEL INTERACTIONS WITH DISOPYRAMIDE AND QUINIDINE( CHANNEL BLOCKADE )

In voltage-clamp studies of atrial myocytes exposed to disopyramide or quinidine, pulse-train stimulation revealed use-dependent block that increased with increased pulse amplitude. Use-dependent block also bec ame negligible at hyperpolarized holding potentials (< -150 mV), consi stent with either rapid unbinding at the holding potential or trapping of the drug in a drug-complexed rest conformation followed by rapid u nbinding during the next channel opening event. To explore the unbindi ng properties of hypothetically different rest-blocked conformations, we exposed cells to a postdepolarization ''conditioning'' potential af ter channels had become fully inactivated so as to vary the transition to different hypothetical rest-blocked channels. Pulse-train stimulat ion from -130 to -30 mV generated only a small amount of use-dependent block. Inserting a 120-ms subthreshold (e.g., -100 mV) postdepolariza tion conditioning potential before return to -130 mV increased use-dep endent block. The fraction of steady-state block exhibited a bell-shap ed dependence on the conditioning potential. These results are consist ent with the existence of a mixture of rest-blocked channel conformati ons, each having direct access to the blocked-inactivated state. These intermediate rest conformations display radically different drug unbi nding rates.