Tsurugi Takuo, Nagatomo Toshihisa, Abe Haruhiko, Oginosawa Yasushi, Takemasa Hiroko, Kohno Ritsuko, Makita Naomasa, Makielski Jonathan C, Otsuji Yutaka
Second Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu 807-8555, Japan.
Life Sci. 2009 Mar 13;84(11-12):380-7. doi: 10.1016/j.lfs.2009.01.001. Epub 2009 Jan 9.
In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by beta-adrenergic agents produces similar effects on the late sodium current (I(Na)) to those by overdrive pacing therapy. We analyzed the beta-adrenergic-like effects of protein kinase A and fluoride on I(Na) in R1623Q mutant channels.
cDNA encoding either wild-type (WT) or R1623Q mutant of hNa(v)1.5 was stably transfected into HEK293 cells. I(Na) was recorded using a whole-cell patch-clamp technique at 23 degrees C.
In R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late I(Na) in a time-dependent manner. Modulations of peak I(Na) gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of beta-adrenergic stimulation by analyzing the frequency-dependence of the late I(Na). Fluoride augmented frequency-dependent reduction of the late I(Na), which was due to preferential delay of recovery of late I(Na). However, the increase in late I(Na) by fluoride at steady-state was more potent than the frequency-dependent reduction of late I(Na).
Different basic mechanisms participate in the QT interval shortening by pacing and beta-adrenergic stimulation in the LQT3.
在3型长QT综合征（LQT3）中，通过超速起搏缩短QT间期可用于预防危及生命的心律失常。然而，尚不清楚β-肾上腺素能药物诱导的心率加快对晚钠电流（I(Na)）产生的影响是否与超速起搏治疗产生的影响相似。我们分析了蛋白激酶A和氟化物对R1623Q突变通道中I(Na)的β-肾上腺素能样作用。
将编码野生型（WT）或hNa(v)1.5的R1623Q突变体的cDNA稳定转染到HEK293细胞中。在23℃下使用全细胞膜片钳技术记录I(Na)。
在R1623Q通道中，2 mM pCPT-AMP和120 mM氟化物以时间依赖性方式显著延迟宏观电流衰减并增加晚I(Na)的相对幅度。氟化物对WT和R1623Q通道中I(Na)峰值门控动力学（激活、失活、从失活中恢复）的调节相似。同时用蛋白激酶抑制剂透析几乎完全消除了氟化物的作用。我们还通过分析晚I(Na)的频率依赖性，比较了起搏与β-肾上腺素能刺激的效果。氟化物增强了晚I(Na)的频率依赖性降低，这是由于晚I(Na)恢复的优先延迟。然而，氟化物在稳态时对晚I(Na)的增加作用比晚I(Na)的频率依赖性降低更强。
在LQT3中，起搏和β-肾上腺素能刺激导致QT间期缩短的基本机制不同。
