title: Open Na+ channel blockade: multiple rest states revealed by channel interactions with disopyramide and quinidine.
abstract: 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 became negligible at hyperpolarized holding potentials (< -150 mV), consistent with either rapid unbinding at the holding potential or trapping of the drug in a drug-complexed rest conformation followed by rapid unbinding during the next channel opening event. To explore the unbinding properties of hypothetically different rest-blocked conformations, we exposed cells to a postdepolarization "conditioning" potential after channels had become fully inactivated so as to vary the transition to different hypothetical rest-blocked channels. Pulse-train stimulation from -130 to -30 mV generated only a small amount of use-dependent block. Inserting a 120-ms subthreshold (e.g., -100 mV) postdepolarization conditioning potential before return to -130 mV increased use-dependent block. The fraction of steady-state block exhibited a bell-shaped dependence on the conditioning potential. These results are consistent with the existence of a mixture of rest-blocked channel conformations, each having direct access to the blocked-inactivated state. These intermediate rest conformations display radically different drug unbinding rates.
authors.affiliation: Department of Medicine (Cardiology), Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Y I
authors.initials: YI
authors.lastname: Zilberter
authors.forename: C F
authors.initials: CF
authors.lastname: Starmer
authors.forename: A O
authors.initials: AO
authors.lastname: Grant
mesh_terms: D000818:Animals; D004206:Disopyramide / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008433:Mathematics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D011802:Quinidine / Q000494:pharmacology*; D011817:Rabbits; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D004206:Disopyramide; D011802:Quinidine