Open Na+ channel blockade: multiple rest states revealed by channel interactions with disopyramide and quinidine
| Autor: | C F Starmer, Yuri Zilberter, Augustus O. Grant |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Quinidine
Physiology Guinea Pigs Kinetics Stimulation In Vitro Techniques Sodium Channels Membrane Potentials Sodium channel blocker Physiology (medical) medicine Animals Membrane potential Sodium channel Heart Electric Stimulation Blockade Anesthesia Biophysics Rabbits Cardiology and Cardiovascular Medicine Disopyramide Ion Channel Gating Mathematics Sodium Channel Blockers medicine.drug |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 266:H2007-H2017 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.1994.266.5.h2007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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