title: Kinetics of interaction of disopyramide with the cardiac sodium channel: fast dissociation from open channels at normal rest potentials.
abstract: Block of cardiac sodium channels is enhanced by repetitive depolarization. It is not clear whether the changes in drug binding result from a change in affinity that is dependent on voltage or on the actual state of the channel. This question was examined in rabbit ventricular myocytes by analyzing the kinetics of block of single sodium channel currents with normal gating kinetics or channels with inactivation and deactivation slowed by pyrethrin toxins. At -20 and -40 mV, disopyramide 100 microM blocked the unmodified channel. Mean open time decreased 45 and 34% at -20 and -40 mV during exposure to disopyramide. Exposure of cells to the pyrethrin toxins deltamethrin or fenvalrate caused at least a tenfold increase in mean open time, and prominent tail currents could be recorded at the normal resting potential. The association rate constant of disopyramide for the normal and modified channel at -20 mV was similar, approximately 10 x 10(6)/M/sec. During exposure to disopyramide, changes in open and closed times and in open channel noise at -80 and -100 mV are consistent with fast block and unblocking events at these potentials. This contrasts with the slow unbinding of drug from resting channels at similar potentials. We conclude that the sodium channel state is a critical determinant of drug binding and unbinding kinetics.
authors.affiliation: Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina 27706.
authors.forename: A O
authors.initials: AO
authors.lastname: Grant
authors.forename: D J
authors.initials: DJ
authors.lastname: Wendt
authors.forename: Y
authors.initials: Y
authors.lastname: Zilberter
authors.forename: C F
authors.initials: CF
authors.lastname: Starmer
mesh_terms: D000818:Animals; D004206:Disopyramide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009570:Nitriles; D011722:Pyrethrins / Q000494:pharmacology; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: D009570:Nitriles; D011722:Pyrethrins; D015222:Sodium Channels; C017180:decamethrin; D004206:Disopyramide