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.

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.

• Authors: Naoki Aizawa, Yoshikazu Fujimori, Osamu Nakanishi, Takemitsu Hayashi, Yoshiaki Goi, Jun-Ichi Kobayashi, Tomoe Fujita
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 899 Pg. 173995 (May 15 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 33675781 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Acetanilides
• Adrenergic beta-3 Receptor Agonists
• Muscarinic Antagonists
• Receptors, Adrenergic, beta-3
• TRPM Cation Channels
• Thiazoles
• Trpm8 protein, rat
• Tolterodine Tartrate
• Cyclic AMP
• mirabegron

Topics

• 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, metabolism)
• TRPM Cation Channels (antagonists & inhibitors, metabolism)
• Thiazoles (pharmacology)
• Tolterodine Tartrate (pharmacology)
• Urinary Bladder (drug effects, metabolism, physiopathology)
• Urinary Bladder, Overactive (drug therapy, etiology, metabolism, physiopathology)
• Urodynamics (drug effects)
• Rats