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长期使用阿米奥达龙可以重塑老鼠心脏中离子通道转录的表达
Sabrina Le Bouter1, Aziza El Harchi, Céline Marionneau
1Institut du thorax, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes Cedex, France.
Circulation
|November 3, 2004
概括
长期的阿米奥达龙治疗会改变小鼠的离子通道基因表达,影响心脏功能. 这种药物基因组改造有助于该药物除了甲状腺激素变化之外的抗失律作用.
科学领域:
- 药物基因组学 药物基因组学
- 心血管药理学心血管药理学
- 分子心脏病学分子心脏病学
背景情况:
- 在治疗心律失常时,阿米奥达龙的有效性背后的确切机制尚不清楚.
- 这项研究探讨了阿米奥达龙对负责离子通道子单元的基因的药物基因学影响.
研究的目的:
- 在小鼠模型中研究阿米奥达龙对离子通道基因表达的剂量依赖影响.
- 为了将这些分子变化与观察到的电生理学效应相关联.
主要方法:
- 成年雄性小鼠接受了阿米奥达龙 (30-180毫克/公斤/天) 或载体6周.
- 分析了血和心肌药物水平,甲状腺激素水平,心电图和基因表达 (离子芯片,RT-PCR).
- 补丁电生理学被用来评估离子通道电流.
主要成果:
- 阿米奥达龙治疗导致药物水平的剂量依赖性增加和延长的心电图间隔 (RR,PR,QRS,QT).
- 观察到Na+,Ca2+和K+通道 (如SCN5A,CaCNA1C,KCNA5) 的基因下调和其他基因 (如KCNA4,KCNK1) 的上调.
- 减少的离子通道电流 (I~to,f),I~K,缓慢),I~Na) 与调低的基因表达相关.
结论:
- 长期使用阿米奥达龙会诱导离子通道表达的剂量依赖的重塑,与电生理学变化相关.
- 这些转录基因变化有助于阿米奥达龙的治疗效果,独立于它对甲状腺激素的影响.
- 阿米奥达龙的抗失律作用包括直接的膜效应和对离子通道基因表达的调制.
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