探索细胞外pH值和Dronedarone对心脏功能的药理作用之间的相互作用
Michael Ramon de Lima Conceição1, Jorge Lucas Teixeira-Fonseca1, Diego Jose Belato Orts1
1Laboratório de CardioBiologia, Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.
细胞外pH值会影响无人机 (DRN) 对心脏通道 (Nav1.5) 和电活动的作用. 这种依赖pH的作用会影响其治疗心律失常的有效性.
科学领域:
- 心血管药理学心血管药理学
- 电子生理学 电子生理学
- 生物物理学的生物物理.
背景情况:
- 德罗内达龙 (DRN) 是一种针对心脏通道的抗节律药物.
- 已知细胞外pH (pHe) 会改变药物道相互作用.
- 对于pHe对DRN与Nav1.5的相互作用的影响尚不完全理解.
研究的目的:
- 为了研究细胞外pH值如何调节dronedarone对Na1.5电流的药理作用.
- 评估pHe对DRN在心脏准备中的作用的影响.
主要方法:
- 人类胚胎细胞 (HEK293T/17) 表达Nav1.5被用于补丁研究.
- 晚期电流 (INaLate) 是使用神经毒素-II (ATX-II) 诱导的.
- 活体Langendorff输入的Wistar老鼠心脏被用于记录心电图 (ECG).
主要成果:
- 德罗内达龙首选结合于pHe 7.0.0 的封闭无活化状态的Na1.5
- DRN延迟了Nav1.5无活化后的恢复,并在pHe 7.0与7.4.4之间表现出明显的使用依赖性质.
- 峰值INa,激活,非激活曲线,以及DRN的INaLate阻断没有被pHe显著改变.
- DRN以度和pH值依赖的方式调节了心电图参数 (QRS,QT,RR间隔).
结论:
- 无人机对Na1.5和心脏电功能的药理特征和生物效应部分取决于细胞外pH值.
- 在相关度下,pH值的变化可能会改变dronedarone的临床疗效.
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