title: Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.
abstract: A number of basic and clinical studies suggest that elevation of external sodium concentrations, [Na]o, may reverse the cardiotoxic effect of local anesthetic-class drugs. The mechanisms of reversal are uncertain. The blocking action of lidocaine and disopyramide were studied over a range of [Na]o. Both whole-cell voltage clamp and single-channel recordings were performed on isolated rabbit myocytes at 17 and 22 degrees C, respectively. In the presence of lidocaine, an inactivated channel blocker, the level of steady-state block in response to pulse train stimulation was not affected by variations in [Na]o from 20 to 150 mM. Estimates of the rate of dissociation of drug from the channel also were unaffected. In contrast, steady-state block by disopyramide, a drug that blocks open channels, was decreased as [Na]o was increased. Single-channel measurements suggest that the influence of [Na]o on channel current amplitude was small, 12% for a 25 mM increase in [Na]o. This increase in single-channel current amplitude would affect drug-free channels only, in that our studies suggest that drug-associated channels do not conduct. The association rate constant of disopyramide with open single sodium channels was decreased from 10 x 10(6) to 5 x 10(6)/M per s by an increase in [Na]o from 120 to 180 mM. Elevation of [Na]o may reverse the blocking action of local anesthetic-class drugs by an increase in single-channel current amplitude or by a decrease in drug association rate with the sodium channel. The occurrence of the latter action depends on the mode of block of the specific agent.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27706.
authors.forename: M J
authors.initials: MJ
authors.lastname: Barber
authors.forename: D J
authors.initials: DJ
authors.lastname: Wendt
authors.forename: C F
authors.initials: CF
authors.lastname: Starmer
authors.forename: A O
authors.initials: AO
authors.lastname: Grant
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004206:Disopyramide / Q000494:pharmacology*; D004553:Electric Conductivity; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D011817:Rabbits; D012964:Sodium / Q000502:physiology*; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D015222:Sodium Channels; D008012:Lidocaine; D012964:Sodium; D004206:Disopyramide