KPR-5714, a Novel Transient Receptor Potential Melastatin 8 Antagonist, Improves Overactive Bladder via Inhibition of Bladder Afferent Hyperactivity in Rats
| Autor: | Mutai Yosuke, Yoshikazu Fujimori, Fumiya Tanada, Yasuhiko Igawa, Hideaki Hirasawa, Osamu Nakanishi, Naoki Aizawa, Akane Matsuzawa, Takemitsu Hayashi, Jun-ichi Kobayashi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Urinary Bladder TRPM Cation Channels Urination Pharmacology urologic and male genital diseases Frequent urination Rats Sprague-Dawley 03 medical and health sciences Transient receptor potential channel 0302 clinical medicine Dorsal root ganglion medicine TRPM8 Animals Humans Afferent Pathways Urinary bladder Urinary Bladder Overactive business.industry Antagonist Cerebral Infarction medicine.disease female genital diseases and pregnancy complications Rats HEK293 Cells 030104 developmental biology medicine.anatomical_structure Overactive bladder Molecular Medicine Female Mechanosensitive channels medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 373:239-247 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB. SIGNIFICANCE STATEMENT: TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder. |
| Databáze: | OpenAIRE |
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