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A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels
R S Sheldon1, N J Cannon, H J Duff
1Department of Medicine, University of Calgary, Faculty of Medicine, Alberta, Canada.
Abstract:
We assessed the effects of type I antiarrhythmic drugs on the binding of ligands to receptors on voltage-sensitive sodium channels of rat cardiac myocytes. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTXB), a toxin that binds to the sodium channel. The 8 drugs tested inhibited [3H]BTXB binding in a dose-dependent fashion with IC50 values from 1.34 microM for O-demethylencainide to 811 microM for procainamide. A log-log plot of IC50 versus mean therapeutic serum concentration yielded a regression line with slope of 1.17 and r of 0.95. Scatchard analysis of [3H]BTXB binding showed that lidocaine reduced the maximal binding without altering the KD for [3H]BTXB binding, indicating allosteric inhibition. The inhibition by lidocaine of [3H]BTXB binding was reversible within 30 minutes when the samples were diluted from 390 to 39 microM lidocaine. In other studies, the stereoisomers of tocainide were shown to have a threefold to fourfold difference in IC50 for inhibition of [3H]BTXB binding. The binding of antiarrhythmic drugs to this site is saturable, reversible, and stereospecific and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. This suggests that binding at this site relates to pharmacologic activity.
Insights
Type I antiarrhythmic drugs bind to voltage-sensitive sodium channels, affecting their function. This binding occurs at relevant concentrations and correlates with drug potency, suggesting a key mechanism for antiarrhythmic activity.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Molecular Biology
Background:
- Voltage-sensitive sodium channels are critical for cardiac action potentials.
- Type I antiarrhythmic drugs modulate cardiac electrophysiology.
- Understanding drug-receptor interactions is key to antiarrhythmic drug development.
Purpose of the Study:
- To investigate the binding of type I antiarrhythmic drugs to voltage-sensitive sodium channels.
- To determine the affinity and mechanism of drug binding.
- To correlate binding characteristics with in vivo pharmacological activity.
Main Methods:
- Radioligand binding assays using [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTXB).
- Dose-response inhibition studies to determine IC50 values.
- Scatchard analysis to characterize binding kinetics (KD, Bmax).
- Assessment of binding reversibility and stereospecificity.
Main Results:
- Eight type I antiarrhythmic drugs inhibited [3H]BTXB binding in a dose-dependent manner.
- IC50 values ranged from 1.34 microM (O-demethylencainide) to 811 microM (procainamide).
- Lidocaine demonstrated allosteric inhibition by reducing maximal binding (Bmax) without affecting the dissociation constant (KD).
- Binding was found to be saturable, reversible, and stereospecific.
- A strong correlation (r=0.95) was observed between IC50 and mean therapeutic serum concentrations.
Conclusions:
- Type I antiarrhythmic drugs bind to a specific site on voltage-sensitive sodium channels.
- This binding occurs at pharmacologically relevant concentrations.
- The binding characteristics (affinity, mechanism, stereospecificity) are closely related to the drugs' in vivo antiarrhythmic potency.