Efficacy of the combination of KPR-5714, a novel transient receptor potential melastatin 8 (TRPM8) antagonist, and β3-adrenoceptor agonist or anticholinergic agent on bladder dysfunction in rats with bladder overactivity
| Autor: | Takemitsu Hayashi, Jun-ichi Kobayashi, Tomoe Fujita, Yoshiaki Goi, Naoki Aizawa, Osamu Nakanishi, Yoshikazu Fujimori |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist business.industry medicine.drug_class Antagonist Tolterodine Tartrate urologic and male genital diseases medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Overactive bladder medicine TRPM8 Anticholinergic business Mirabegron Urinary bladder disease 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | European Journal of Pharmacology. 899:173995 |
| ISSN: | 0014-2999 |
| Popis: | Transient receptor potential melastatin 8 (TRPM8) channels may contribute to the pathophysiological bladder afferent hyperactivity, thus a TRPM8 antagonist would be a promising therapeutic target for the bladder hypersensitive disorders including urinary urgency in overactive bladder (OAB). We aimed to investigate a pharmacological effect of KPR-5714, a novel selective TRPM8 antagonist, on TRPM8 channels, M3 receptors and β3-adrenoceptors using the transfected cells of each gene at first. Then, combination effects of KPR-5714 and mirabegron, a β3-adrenoceptor agonist, or tolterodine tartrate, an anticholinergic agent, were studied on rhythmic bladder contractions (RBCs) in normal rats and bladder function in frequent-voiding rats. In vitro measurements showed that KPR-5714 acts on neither β3-adrenoceptor nor M3 receptor. In normal rats, KPR-5714 and mirabegron significantly reduced the frequency of RBCs, and a combined administration showed an additive effect. In rats with cerebral infarction, KPR-5714 and mirabegron significantly reduced the voiding frequency, and a combined administration showed an additive effect. In rats exposed to cold temperature, KPR-5714 and tolterodine tartrate significantly reduced the voiding frequency accompanied by the increased mean voided volume, and a combined administration showed additive effects. The present study demonstrated that the combined administration of KPR-5714 and mirabegron or tolterodine tartrate showed the additive effects on bladder dysfunction in different animal models, suggesting that the combination therapy of TRPM8 antagonist and β3-adrenoceptor agonist or anticholinergic agent can be the potential treatment option for obtaining additive effects in comparison with monotherapy for OAB. |
| Databáze: | OpenAIRE |
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