Retigabine stimulates human KCNQ2/Q3 channels in the presence of bupivacaine
Retigabine stimulates human KCNQ2/Q3 channels in the presence of bupivacaine
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DOI：
10.1097/00000542-200408000-00024
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发表时间：
2004-08-01
期刊：
影响因子：
8.8
通讯作者：
Friederich, P
中科院分区：
文献类型：
--
作者：
Punke, MA;Friederich, P
背景：KCNQ 2/Q3通道的抑制可能导致人类惊厥。布比卡因与这些通道的相互作用是未知的。抗惊厥药瑞替加滨激活KCNQ 2/Q3通道，并可能逆转布比卡因的抑制作用。因此，钾通道刺激可能构成一种新的方法来治疗局部麻醉诱导的癫痫发作。本研究的目的是表征布比卡因对KCNQ 2/Q3通道的影响，并探讨瑞替加滨是否逆转了局部麻醉剂的影响。方法：KCNQ 2/Q3通道在中国仓鼠卵巢细胞中瞬时表达。结果：布比卡因对KCNQ 2/Q 3通道的抑制作用呈浓度依赖性，且可逆。通过Hill方程描述浓度-响应曲线（IC 50 = 173 +/- 7 μ m，Hill系数= 1.4 +/- 0.1，平均值+/- SEM，n = 37）。布比卡因和左旋布比卡因的抑制作用无显著性差异（42 ± 4%，n = 7; 42 5%，n = 10; P > 0.05）。罗哌卡因的效力比布比卡因低四倍。布比卡因对KCNQ 2/Q3通道的抑制可导致细胞膜电位的可逆性去极化。Retigabine（300 nM-10 μ M）逆转布比卡因对KCNQ 2/Q3通道的抑制作用以及膜电位的去极化。结论：纳摩尔浓度的抗惊厥剂Retigabine逆转布比卡因微摩尔浓度的抑制作用。我们的研究结果允许这样的假设，即瑞替加滨激活KCNQ 2/Q3通道可能为治疗布比卡因诱导的癫痫发作提供一种新的治疗方法。
Background: Inhibition of KCNQ2/Q3 channels may cause convulsion in humans. The interaction of bupivacaine with these channels is unknown. The anticonvulsant retigabine activates KCNQ2/Q3 channels and may reverse inhibitory actions of bupivacaine. Potassium channel stimulation may thus constitute a novel approach to treat local anesthetic-induced seizures. The aim of this study was to characterize bupivacaine effects on KCNQ2/Q3 channels and to investigate whether retigabine reverses the effects of the local anesthetic.Methods: KCNQ2/Q3 channels were transiently expressed in Chinese hamster ovary cells. The effects of bupivacaine and retigabine were studied with the patch-clamp technique.Results: Bupivacaine inhibited KCNQ2/Q3 channels in a concentration-dependent and reversible manner. The concentration-response curve was described by a Hill equation (IC50 = 173 +/- 7 mum, Hill coefficient = 1.4 +/- 0.1, mean +/- SEM, n = 37). The inhibitory effect did not differ between bupivacaine and levobupivacaine (42 +/- 4%, n = 7, versus 42 5%, n = 10; P > 0.05). Ropivacaine was four times less potent than bupivacaine. The inhibition of KCNQ2/Q3 channels by bupivacaine resulted in a significant and reversible depolarization of the membrane potential. Retigabine (300 nM-10 muM) reversed the inhibitory action of bupivacaine on KCNQ2/Q3 channels as well as the depolarization of the membrane potential.Conclusions: The anticonvulsant retigabine at nanomolar concentrations reverses the inhibitory effect of micromolar concentrations of bupivacaine. Our results allow the hypothesis that activation of KCNQ2/Q3 channels by retigabine may offer a novel therapeutic approach for the treatment of bupivacaine-induced seizures.