Open Na+ channel blockade: multiple rest states revealed by channel interactions with disopyramide and quinidine.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zilberter, YI; Starmer, CF; Grant, AO

Published Date

  • May 1994

Published In

Volume / Issue

  • 266 / 5 Pt 2

Start / End Page

  • H2007 - H2017

PubMed ID

  • 8203599

Pubmed Central ID

  • 8203599

Electronic International Standard Serial Number (EISSN)

  • 2163-5773

International Standard Serial Number (ISSN)

  • 0002-9513

Digital Object Identifier (DOI)

  • 10.1152/ajpheart.1994.266.5.h2007

Language

  • eng