Advertisement
Research Article Free access | 10.1172/JCI115871
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27706.
Find articles by Barber, M. in: JCI | PubMed | Google Scholar
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27706.
Find articles by Wendt, D. in: JCI | PubMed | Google Scholar
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27706.
Find articles by Starmer, C. in: JCI | PubMed | Google Scholar
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27706.
Find articles by Grant, A. in: JCI | PubMed | Google Scholar
Published August 1, 1992 - More info
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.