Capsazepine prolongation of the duration of lidocaine block of sensory transmission in mice may be mediated by modulation of HCN channel currents
Capsazepine prolongation of the duration of lidocaine block of sensory transmission in mice may be mediated by modulation of HCN channel currents
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辣椒西平延长利多卡因阻断小鼠感觉传递的持续时间可能是通过调节 HCN 通道电流介导的
作者：
Zhao Wenling;Liang Peng;Liu Jin;Li Huan;Liao Daqing;Chen Xiangdong;Li Qian;Zhou Cheng
背景与目的超极化激活环核苷酸门控(HCN)通道参与利多卡因的作用。辣椒素的竞争性抑制剂Capsazepine(CPZ)也能抑制HCN通道电流(Ih)。本研究旨在探讨CPZ能否延长利多卡因在区域麻醉中的使用时间。方法在人胚胎肾293(HEK 293)细胞中表达小鼠HCN1和HCN2通道。采用全细胞膜片钳记录技术检测CPZ对Ih的影响。采用小鼠坐骨神经阻滞模型进行体内研究。将小鼠随机分为7组，分别给予利多卡因、CPZ、HCN通道阻滞剂ZD7288、CPZ+利多卡因、ZD7288+利多卡因、ZD7288+CPZ+利多卡因、腺苷环化酶激活剂福司可林+CPZ+利多卡因。测定利多卡因局部麻醉持续时间。在小鼠背根神经节神经元上记录到电压门控性钠通道电流(INa)和Ih。观察CPZ对环磷酸腺苷(CAMP)和环磷酸腺苷(CAMP)作用后INA和Ih的变化。分离小鼠坐骨神经，观察CPZ对复合动作电位(CAP)的影响。结果卡萨西平非选择性地抑制HEK 293细胞的mHCN1和mHCN2通道电流。在体内坐骨神经阻滞中，与单纯利多卡因相比，CPZ延长了利多卡因对伤害性感觉阻滞(35.1±3.3vs.20.3±1.7min)、触觉感觉阻滞(25.5±4.4vs.20.0±3.7min)、热感觉阻滞(39.6±6.6vs.26.8±5.5min)和运动功能阻滞(28.6±4.1vs.20.9±4.2min)的作用时间。CPZ+利多卡因组的感觉传导时间明显长于ZD7288+利多卡因组(39.6±6.6min比33.4±4.5min)。Forsklin可逆转CPZ延长利多卡因持续时间的作用。CPZ或ZD7288单独应用不能产生典型的局部麻醉效果。细胞内cAMP浓度升高可逆转CPZ对Ih的抑制作用。CPZ单独抑制30μM以上的INA，但对坐骨神经CAP波幅无抑制作用。CPZ可剂量依赖性地增强1%利多卡因对CAP波幅的抑制作用。结论卡萨西平可能通过调节HCN通道电流而延长利多卡因在周围神经阻滞的持续时间。
Background and objectives Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels contribute to the effects of lidocaine. Capsazepine (CPZ), a competitive inhibitor of capsaicin of transient receptor potential vanilloid-1 channel, has also been found to inhibit HCN channel currents (Ih). This study was designed to investigate whether CPZ could prolong durations of lidocaine in regional anesthesia. Methods Mouse HCN1 and HCN2 channels were expressed in human embryonic kidney 293 (HEK 293) cells. The effect of CPZ on Ih was measured by whole-cell patch-clamping recording. Sciatic nerve block model in mice was used for the study in vivo. The mice were randomly divided into seven groups, respectively, receiving lidocaine, CPZ, ZD7288 (HCN channel blocker), CPZ + lidocaine, ZD7288 + lidocaine, ZD7288 + CPZ + lidocaine, forskolin (an activator of adenylyl cyclase) + CPZ + lidocaine. Regional anesthetic durations of lidocaine were determined. Voltage-gated sodium channel currents (INa) and Ih were recorded in dorsal root ganglion neurons of mice. The effects of CPZ on INa and Ih with or without Cyclic adenosine monophosphate (cAMP) were assessed. Isolated mice sciatic nerve was prepared to evaluate the effect of CPZ on the compound action potentials (CAP). Results Capsazepine non-selectively inhibited transfected mHCN1 and mHCN2 channel currents in HEK 293 cells. In sciatic nerve block in vivo, compared to lidocaine alone, adding CPZ extended the durations of lidocaine for noxious sensory block (35.1 ± 3.3 vs. 20.3 ± 1.7 min), tactile sensory block (25.5 ± 4.4 vs. 20.0 ± 3.7 min), thermal sensory block (39.6 ± 6.6 vs. 26.8 ± 5.5 min), and motor function block (28.6 ± 4.1 vs. 20.9 ± 4.2 min). Duration of thermal sensory block was longer in CPZ + lidocaine group than that of ZD7288 + lidocaine group (39.6 ± 6.6 vs. 33.4 ± 4.5 min). Forskolin reversed the prolongation by CPZ on lidocaine durations. CPZ or ZD7288 alone did not produce typical regional anesthetic effects. Increased intracellular concentration of cAMP reversed the inhibition of CPZ on Ih. Although CPZ alone inhibited INa at the concentration more than 30 μM, it did not inhibit the CAP amplitudes in isolated sciatic nerves. CPZ dose-dependently enhanced the inhibitory effect of 1% lidocaine on the CAP amplitudes. Conclusions Capsazepine may prolong durations of lidocaine in peripheral nerve block by modulation of HCN channel currents.
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影响因子：
5.3
作者：
Cui, M.;Honore, P.;Faltynek, C. R.
通讯作者：
Faltynek, C. R.
影响因子：
64.8
作者：
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通讯作者：
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影响因子：
5
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影响因子：
5.1
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通讯作者：
Tomotsugu Yamada;Maiko Hasegawa-Moriyama;Tae Kurimoto;Takayuki Saito;T. Kuwaki;Y. Kanmura
影响因子：
16.2
作者：
Peters, James H.;McDougall, Stuart J.;Fawley, Jessica A.;Smith, Stephen M.;Andresen, Michael C.
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