A paradoxical effect of lidocaine for the N406S mutation of SCN5A associated with Brugada syndrome.

Abstract

BACKGROUND:

Accelerated intermediate inactivation, which is caused by mutations in the cardiac voltage-gated sodium channel alpha-subunit gene (SCN5A), is one of the molecular mechanisms underlying Brugada syndrome. The N406S mutation associated with Brugada syndrome results in the accelerated intermediate inactivation, in addition to unique pharmacological characteristics.

METHODS:

Functional sodium channels were expressed transiently in HEK293 cells by transfecting equally the alpha- and beta-subunit plasmids (1 microg/ml) and the sodium current were measured in whole-cell mode of patch-clamp recording.

RESULTS:

Since the N406S mutant channel has a greatly reduced use-dependent block of lidocaine, we took the advantage of the mutant channel to examine the effect of lidocaine on intermediate inactivation using wild-type (WT) and N406S mutant channels recombinantly expressed in HEK293 cells. Lidocaine (100 microM) slowed the recovery from the fast inactivation similarly for WT and N406S. On the other hand, whereas lidocaine slowed the recovery from the intermediate inactivation for WT, lidocaine accelerated the recovery for N406S. Activity-dependent loss of channel availability by repetitive 500-ms pulses was more strongly enhanced and accelerated by lidocaine for WT, but lidocaine exerted little effect on the N406S channel.

CONCLUSION:

We demonstrate that lidocaine may suppress Brugada syndrome associated with the N406S mutation by preventing the sodium channel from accumulating in the intermediate inactivation state.

• Authors: Hideki Itoh, Keiko Tsuji, Tomoko Sakaguchi, Iori Nagaoka, Yuko Oka, Yuko Nakazawa, Takenori Yao, Hikari Jo, Takashi Ashihara, Makoto Ito, Minoru Horie, Keiji Imoto
• Journal: International journal of cardiology (Int J Cardiol) Vol. 121 Issue 3 Pg. 239-48 (Oct 18 2007) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 17445919 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Muscle Proteins
• NAV1.5 Voltage-Gated Sodium Channel
• SCN5A protein, human
• Sodium Channels
• Lidocaine

Topics

• Anti-Arrhythmia Agents (pharmacology)
• Brugada Syndrome (drug therapy, genetics)
• Computer Simulation
• Genetic Predisposition to Disease
• Humans
• Lidocaine (pharmacology)
• Male
• Markov Chains
• Muscle Proteins (genetics)
• Mutation, Missense
• NAV1.5 Voltage-Gated Sodium Channel
• Patch-Clamp Techniques
• Sodium Channels (drug effects, genetics)