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

详细信息    查看全文

• 作者：Hideki Itoh ; Keiko Tsuji ; Tomoko Sakaguchi ; Iori Nagaoka ; Yuko Oka ; Yuko Nakazawa ; Takenori Yao ; Hikari Jo ; Takashi Ashihara ; Makoto Ito ; Minoru Horie ; Keiji Imoto
• 关键词：Brugada syndrome ; Sodium channel ; SCN5A ; Lidocaine ; Inactivation
• 刊名：International Journal of Cardiology
• 出版年：2007
• 出版时间：18 October 2007
• 年：2007
• 卷：121
• 期：3
• 页码：239-248
• 全文大小：1238 K

文摘

Accelerated intermediate inactivation, which is caused by mutations in the cardiac voltage-gated sodium channel α-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 α- and β-subunit plasmids (1 μg/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 μM) 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.