Cold stress-induced bladder overactivity in type 2 diabetic mellitus rats is mitigated by the combination of a M3-muscarinic antagonist and a β3-adrenergic agonist

IF 1.5 4区医学 Q3 UROLOGY & NEPHROLOGY

LUTS: Lower Urinary Tract Symptoms Pub Date : 2022-12-21 DOI:10.1111/luts.12472

Hiroaki Hara, Tetsuya Imamura, Ataru Suzuki, Manabu Ueno, Tomonori Minagawa, Teruyuki Ogawa, Osamu Ishizuka

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Abstract

Objectives

Goto-Kakizaki (GK) rats with type 2 diabetes mellitus respond to low temperature (LT) environments with bladder overactivity, including increased voiding frequency and decreased voiding interval and micturition volume. We determined if bladder overactivity could be inhibited by treatment with the combination of a M₃-muscarinic receptor antagonist and a β₃-adrenergic receptor agonist.

Methods

Ten-week-old female GK rats were fed a high-fat diet for 4 weeks. Cystometric investigations were conducted at room temperature (RT, 27 ± 2°C). The rats were then intraperitoneally administered the vehicle, the M₃-muscarinic receptor antagonist solifenacin, the β₃-adrenergic agonist mirabegron, or a combination of solifenacin and mirabegron. Ten minutes after the administrations, the rats were transferred to the LT environment (4 ± 2°C), where the cystometric measurements were continued. The expressions of both M₃-muscarinic and β₃-adrenergic receptors were investigated.

Results

After transfer from RT to LT, both voiding interval and bladder capacity of the vehicle-, solifenacin-, or mirabegron-treated rats were significantly decreased. However, the combination of solifenacin and mirabegron significantly mitigated the bladder overactivity. While both M₃-muscarinic and β₃-adrenergic receptors were detected, the expression of M₃-muscarinic receptor mRNA was significantly higher than that of β₃-adrenergic receptor mRNA.

Conclusions

The cold stress-induced bladder overactivity was not improved by either the M₃-muscarinic receptor antagonist or the β₃-adrenergic receptor agonist alone. However, the combined treatment mitigated the cold stress responses. Combined therapy with M₃-muscarinic antagonists and β₃-adrenergic agonists could reduce side effects and improve the quality of life for diabetic patients with bladder overactivity.

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M3毒蕈碱拮抗剂和β3-肾上腺素能激动剂联合应用可减轻2型糖尿病大鼠冷应激诱导的膀胱过度活动

目的Goto Kakizaki（GK）2型糖尿病大鼠对低温（LT）环境的反应是膀胱过度活动，包括排尿频率增加、排尿间隔和排尿量减少。我们确定了M3毒蕈碱受体拮抗剂和β3-肾上腺素能受体激动剂的联合治疗是否可以抑制膀胱过度活动。方法10周龄雌性GK大鼠采用高脂饮食喂养4周周。在室温下（RT，27 ± 2°C）。然后对大鼠腹膜内给药载体、M3毒蕈碱受体拮抗剂索非那新、β3-肾上腺素能激动剂米拉贝隆或索非那新和米拉贝隆的组合。给药10分钟后，将大鼠转移到LT环境中（4 ± 2°C），其中继续进行膀胱测量。研究了M3毒蕈碱受体和β3-肾上腺素能受体的表达。结果从RT转为LT后，赋形剂、索非那新或米拉贝隆治疗的大鼠的排尿间隔和膀胱容量均显著降低。然而，索非那新和米拉贝隆的联合用药显著减轻了膀胱过度活动。当同时检测到M3毒蕈碱受体和β3-肾上腺素能受体时，M3毒蕈碱受体mRNA的表达显著高于β3-肾上腺素受体mRNA。结论M3毒蕈碱受体拮抗剂和β3-肾上腺素能受体激动剂均不能改善冷应激引起的膀胱过度活动。然而，联合治疗减轻了冷应激反应。M3毒蕈碱拮抗剂和β3-肾上腺素能激动剂的联合治疗可以减少膀胱过度活动的糖尿病患者的副作用，提高生活质量。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

LUTS: Lower Urinary Tract Symptoms UROLOGY & NEPHROLOGY-

CiteScore

3.00

自引率

7.70%

发文量

审稿时长

>12 weeks

期刊介绍： LUTS is designed for the timely communication of peer-reviewed studies which provides new clinical and basic science information to physicians and researchers in the field of neurourology, urodynamics and urogynecology. Contributions are reviewed and selected by a group of distinguished referees from around the world, some of whom constitute the journal''s Editorial Board. The journal covers both basic and clinical research on lower urinary tract dysfunctions (LUTD), such as overactive bladder (OAB), detrusor underactivity, benign prostatic hyperplasia (BPH), bladder outlet obstruction (BOO), urinary incontinence, pelvic organ prolapse (POP), painful bladder syndrome (PBS), as well as on other relevant conditions. Case reports are published only if new findings are provided. LUTS is an official journal of the Japanese Continence Society, the Korean Continence Society, and the Taiwanese Continence Society. Submission of papers from all countries are welcome. LUTS has been accepted into Science Citation Index Expanded (SCIE) with a 2011 Impact Factor.