title: [Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?].
abstract: 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.
authors.affiliation: Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Yamamoto
authors.forename: Fumio
authors.initials: F
authors.lastname: Soeda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shirasaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahama
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002544:Cerebral Infarction / Q000150:complications; D003915:Dextromethorphan / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D053159:Dysuria / Q000188:drug therapy* / Q000209:etiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology
chemical_list: D000996:Antitussive Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010880:Piperidines; D012701:Serotonin; C040282:cloperastine; D003915:Dextromethorphan