Acute and subacute effects of the selective serotonin-noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels
Acute and subacute effects of the selective serotonin-noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels
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DOI：
10.1007/s00210-013-0878-8
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发表时间：
2013-09-01
影响因子：
3.6
通讯作者：
Scholz, E.
中科院分区：
文献类型：
--
作者：
Fischer, F.;Vonderlin, N.;Scholz, E.
度洛沙汀是一种选择性的阿托宁-去甲肾上腺素再摄取抑制剂，获批用于治疗重度抑郁症。到目前为止，已发现度洛沙汀耐受性良好，报告的心脏副作用可忽略不计。然而，对心脏hERG通道的药理学作用尚未得到适当的解决。hERG通道在非洲爪蟾卵母细胞和人胚肾（HEK）细胞系中表达。采用电压钳和膜片钳技术测量电流。使用Western印迹分析定量通道表面表达。我们发现度洛沙汀以浓度依赖性方式抑制异源表达的hERG通道，在非洲爪蟾卵母细胞中产生的IC 50为142.8 μ M。当使用哺乳动物细胞系时，10或30 μ M度洛沙汀分别导致电流降低34或59%，抑制作用甚至更明显。度洛沙汀不影响通道激活或失活动力学。然而，通道失活被度洛沙汀加速。我们进一步表明，抑制发生在开放和失活状态，但不是关闭状态。阻滞无频率依赖性。然而，当使用hERG孔突变体Y 652 A和F656 A时，度洛沙坦的作用显著减弱。使用Western印迹技术分析度洛沙坦对hERG通道表达的亚急性作用。我们发现，与度洛沙汀孵育导致通道表面表达的浓度依赖性降低。尽管在治疗相关浓度下，度洛沙坦的抑制作用似乎可以忽略不计，但在度洛沙坦过量的情况下以及对药物诱导的QT间期延长敏感的患者给予度洛沙坦时，应考虑hERG阻滞。
Duloxetine is a selective serotonin-noradrenaline reuptake inhibitor approved for treatment of major depressive disorder. So far, duloxetine has been found to be well tolerated and reported cardiac side effects were negligible. However, pharmacological effects on cardiac hERG channels have not been properly addressed yet. hERG channels were expressed in Xenopus oocytes and a human embryonic kidney (HEK) cell line. Currents were measured using voltage clamp and patch clamp techniques. Channel surface expression was quantified using Western blot analysis. We found that duloxetine inhibits heterologously expressed hERG channels in a concentration-dependent manner, yielding an IC50 of 142.8 mu M in Xenopus oocytes. Inhibitory effects were even more pronounced when using a mammalian cell line resulting in a 34 or 59 % current decrease by 10 or 30 mu M duloxetine, respectively. Duloxetine did not affect channel activation or inactivation kinetics. However, channel deactivation was accelerated by duloxetine. We further showed that inhibition occurs in the open and inactivated, but not closed, states. There was no frequency dependence of block. However, effects of duloxetine were significantly attenuated when using the hERG pore mutants Y652A and F656A. Subacute effects of duloxetine on hERG channel expression were analyzed using the Western blot technique. We found that incubation with duloxetine results in a concentration-dependent decrease of channel surface expression. Whereas inhibitory effects of duloxetine seem negligible under therapeutically relevant concentrations, hERG block should be considered in cases of duloxetine overdose and when administering duloxetine to patients susceptible to drug-induced QT prolongation.