Department of Physiology, National Cheng Kung University Medical College, Tainan City 70101, Taiwan.
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan City 70101, Taiwan.
Int J Mol Sci. 2021 Nov 17;22(22):12399. doi: 10.3390/ijms222212399.
Solifenacin (Vesicare, SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K current (I) with effective EC value of 0.34 μM. The activation time constant of I was concurrently shortened in the SOL presence, hence yielding the K value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of I was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of I was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated I; however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in I amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K (K) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the I was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with K channels and hence in stimulating I in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH or mHippoE-14 cells.
索利那新（Vesicare，SOL）是一种异喹啉类化合物，属于毒蕈碱拮抗剂，具有抗胆碱能作用，已被证明可有效治疗尿失禁和神经源性逼尿肌过度活动症。然而，尽管 SOL 在这些疾病的患者中广泛使用，但关于其对膜离子电流影响的信息仍然很大程度上不确定。在这项研究中，全细胞膜电流记录显示，在 GH 细胞的膜去极化时，暴露于 SOL 浓度依赖性地增加了 M 型钾电流（I）的幅度，有效 EC 值为 0.34 μM。在 SOL 存在的情况下，I 的激活时间常数同时缩短，因此根据最小反应方案得出 K 值为 0.55 μM。当细胞暴露于 SOL 时，I 的稳态激活曲线沿电压轴向左移位，而电流的门控电荷不变。在等腰三角形斜坡脉冲下，加入 SOL 会增加 I 的滞后面积。当细胞持续暴露于 SOL 时，进一步应用乙酰胆碱（1 μM）无法改变 SOL 刺激的 I；然而，随后加入促甲状腺素释放激素（TRH，1 μM）能够抵消 SOL 诱导的 I 幅度增加。在细胞贴附式单通道电流记录中，浴液中加入 SOL 导致 M 型钾（K）通道的活性增加，而单通道电导不变；通道的平均开放时间延长。在全细胞膜电流钳记录中，应用 SOL 会减少 GH 细胞中动作电位（AP）的发放；然而，随后加入 TRH 或利诺吡啶能够逆转 SOL 介导的 AP 发放减少。在海马 mHippoE-14 神经元中，加入 SOL 也可刺激 I。总之，这项研究首次揭示了 SOL 与 K 通道相互作用并刺激电兴奋细胞中 I 的有效性，这种明显的作用似乎与其在 GH 或 mHippoE-14 细胞中对经典毒蕈碱受体的拮抗活性无关。
