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Lidocaine block of human heart sodium channels expressed in Xenopus oocytes
M Chahine1, L Q Chen, R L Barchi
1Department of Neurosciences, Roche Institute of Molecular Biology, Nutley, NJ 07110.
Abstract:
The tertiary amine lidocaine is used clinically for preventing cardiac arrhythmias, and has been widely studied on mammalian tissue. Xenopus oocytes were used as an expression system to study the effect of lidocaine on a sodium (Na) channel, derived from a full-length human heart (hH1) cDNA clone. The concentration dependence of the lidocaine block of hH1 Na current was consistent with a binding stoichiometry of 1:1. At low frequency stimulation, and at holding potentials < or = 100 mV, the IC50 was 226 microM, comparable to values found in mammalian cardiac cells. Lidocaine also shifted the steady-state inactivation of hH1 Na current to hyperpolarized potentials in a dose-dependent manner. Our experiments suggest that lidocaine block is state dependent, with high affinity for an inactivated state (KI = 11 microM) and low affinity for the resting state (KR = 3.9 mM). The quaternary amine derivative of lidocaine, QX-314, had no effect on Na current at an extracellular concentration of 1 mM.
Insights
Lidocaine effectively blocks human heart sodium channels in Xenopus oocytes, acting differently on resting and inactivated states. This study clarifies lidocaine
Area of Science:
- Pharmacology
- Molecular Biology
- Cardiovascular Physiology
Background:
- Lidocaine, a tertiary amine, is clinically vital for managing cardiac arrhythmias.
- Previous studies primarily focused on lidocaine's effects on mammalian cardiac tissue.
Purpose of the Study:
- To investigate the effects of lidocaine on human heart sodium channels (hH1) using a Xenopus oocyte expression system.
- To characterize the concentration dependence and state-dependent binding of lidocaine to hH1 sodium channels.
Main Methods:
- Utilized Xenopus oocytes for expressing full-length human heart (hH1) sodium channel cDNA.
- Performed electrophysiological recordings to analyze lidocaine's block of Na current and its effect on channel inactivation.
- Investigated the dose-dependent effects of lidocaine and its quaternary derivative, QX-314.
Main Results:
- Lidocaine demonstrated a 1:1 binding stoichiometry with hH1 sodium channels.
- The IC50 for lidocaine block was 226 microM at low frequency and potentials <= -100 mV, similar to mammalian cardiac cells.
- Lidocaine exhibited state-dependent block, with higher affinity for the inactivated state (KI = 11 microM) than the resting state (KR = 3.9 mM).
- QX-314 showed no effect on Na current at 1 mM extracellular concentration.
Conclusions:
- Lidocaine's interaction with human cardiac sodium channels is state-dependent, favoring the inactivated state.
- The Xenopus oocyte system provides a valuable model for studying ion channel pharmacology.
- Findings contribute to understanding lidocaine's antiarrhythmic mechanisms at the molecular level.