RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats
| Autor: | Hiroyuki Ohshiro, Haruki Kume, Naoki Aizawa, Yukio Homma, Shuzo Watanabe, Yasuhiko Igawa |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment Urinary Bladder TRPM Cation Channels Pharmacology 030226 pharmacology & pharmacy Dinoprostone General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Oxytocics TRPM8 Animals Medicine Neurons Afferent General Pharmacology Toxicology and Pharmaceutics Prostaglandin E2 Saline Cells Cultured Afferent Pathways medicine.diagnostic_test business.industry Urinary Bladder Diseases Antagonist Cystometry General Medicine medicine.disease Rats 030104 developmental biology chemistry business Menthol Urinary bladder disease Body Temperature Regulation medicine.drug Prostaglandin E |
| Zdroj: | Life Sciences. 218:89-95 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2018.12.031 |
| Popis: | Aims To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, on deep body temperature (DBT) and normal bladder sensory function and overactivity and its associated facilitation of mechanosensitive primary bladder single-unit afferent activities (SAAs) induced by intravesical l -menthol or prostaglandin E2 (PGE2) instillation in rats. Main methods The effect of RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was performed on conscious and freely moving rats. SAAs were measured from the left L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity. For both CMG and SAA measurements, after baseline recording with saline instillation, further recording was performed with intravesical l -menthol (6 mM) or PGE2 (60 μM) instillation after pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. Key findings RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 administration increased mean voided volume. Both l -menthol and PGE2 instillation decreased mean voided volume following vehicle pretreatment, whereas such effects were not observed following RQ-00434739 pretreatment. In SAA measurements, either l -menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of Aδ-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly inhibited the l -menthol- and PGE2-induced activation of C-fiber SAAs. Significance The present results demonstrate that blockade of TRPM8 channels can inhibit the pathological activation of mechanosensitive C-fibers and suggest that RQ-00434739 may be a promising therapeutic drug candidate for bladder hypersensitive disorders without affecting DBT. |
| Databáze: | OpenAIRE |
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