論文 - 詳細
| RRC ID | 63866 |
|---|---|
| 著者 | Aizawa N, Fujimori Y, Nakanishi O, Hayashi T, Goi Y, Kobayashi JI, Fujita T. |
| タイトル | 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. |
| ジャーナル | Eur J Pharmacol |
| Abstract |
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. |
| 巻・号 | 899 |
| ページ | 173995 |
| 公開日 | 2021-5-15 |
| DOI | 10.1016/j.ejphar.2021.173995 |
| PII | S0014-2999(21)00148-5 |
| PMID | 33675781 |
| MeSH | Acetanilides / pharmacology* Adrenergic beta-3 Receptor Agonists / pharmacology* Animals Calcium Signaling Cyclic AMP / metabolism Disease Models, Animal Drug Therapy, Combination Female HEK293 Cells Humans Muscarinic Antagonists / pharmacology* Rats, Sprague-Dawley Receptors, Adrenergic, beta-3 / drug effects* Receptors, Adrenergic, beta-3 / metabolism TRPM Cation Channels / antagonists & inhibitors* TRPM Cation Channels / metabolism Thiazoles / pharmacology* Tolterodine Tartrate / pharmacology* Urinary Bladder / drug effects* Urinary Bladder / metabolism Urinary Bladder / physiopathology Urinary Bladder, Overactive / drug therapy* Urinary Bladder, Overactive / etiology Urinary Bladder, Overactive / metabolism Urinary Bladder, Overactive / physiopathology Urodynamics / drug effects* |
| IF | 3.263 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 293T(RCB2202) |