[Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?].
[Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?].
复制标题
[GIRK通道是开发泌尿障碍新型治疗药物的可能靶点吗？]
DOI：
10.1248/yakushi.131.523
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
K. Takahama
中科院分区：
文献类型：
--
作者：
Gen Yamamoto;F. Soeda;T. Shirasaki;K. Takahama
临床上，已知脑梗塞（CI）患者会发生膀胱过度活动症（OAB）和排尿困难。少数抗胆碱能药物用于治疗此类患者的OAB，但效果并不理想。另一方面，针对 CI 后排尿困难的治疗药物很少或根本没有。我们之前报道过右美沙芬（DM）和氯哌斯汀（CP）作为中枢镇咳药，可降低麻醉大鼠的排尿反射频率并增加阈值压力。在本文中，我们描述了 DM 和 CP 对 CI 后 24 小时排尿障碍的影响，这是由左侧大脑中动脉闭塞引起的清醒大鼠。我们还简要回顾了大脑中 G 蛋白偶联内向整流 K(+) (GIRK) 通道的结构、功能和分布，因为这两种药物对大脑神经元中 GIRK 通道激活电流具有有效的抑制作用。在这两种药物中，镇咳有效剂量的 CP 可改善大鼠 CI 后 24 小时的 OAB 和排尿困难。另一方面，DM 加重了排尿困难，尽管它显着改善了 OAB。这些结果提示CP对于治疗CI后OAB和排尿困难可能具有一定的治疗价值。目前，CP 的作用机制尚不清楚。然而，包括药理学研究结果在内的多项证据支持这样的观点，即 CP 的作用可能至少部分是通过对 GIRK 通道激活电流的抑制作用来增加大脑中 5-HT 水平而产生的。
Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents.
影响因子：
14.5
作者：
Athwal, BS;Berkley, KJ;Fowler, CJ
通讯作者：
Fowler, CJ