Muscarinic M3 positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats.

IF 1.5 4区 医学 Q3 UROLOGY & NEPHROLOGY
LUTS: Lower Urinary Tract Symptoms Pub Date : 2022-07-01 Epub Date: 2022-02-12 DOI:10.1111/luts.12430
Risa Okimoto, Katsutoshi Ino, Kenichiro Ishizu, Hajime Takamatsu, Kazuyuki Sakamoto, Hironori Yuyama, Katsunori Imazumi, Akiyoshi Ohtake, Noriyuki Masuda, Masahiro Takeda
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引用次数: 0

Abstract

Objectives: Muscarinic M3 (M3 ) receptors mediate cholinergic smooth muscle contraction of the bladder. Current drugs targeting bladder M3 receptors for micturition disorders have a risk of cholinergic side effects due to excessive receptor activation and insufficient selectivity. We investigated the effect of ASP8302, a novel positive allosteric modulator (PAM) of M3 receptors, on bladder function in rats.

Methods: Modulation of carbachol-induced increases in intracellular Ca2+ was assessed in cells expressing rat muscarinic receptors. Potentiation of bladder contractions was evaluated using isolated rat bladder strips and by measuring intravesical pressure in anesthetized rats. Conscious cystometry was performed to investigate the effects on residual urine volume and voiding efficiency in rat voiding dysfunction models induced by the α1 -adrenoceptor agonist midodrine and muscarinic receptor antagonist atropine, and bladder outlet obstruction. To assess potential side effects, the number of stools and tracheal insufflation pressure were measured in conscious and anesthetized rats, respectively.

Results: ASP8302 demonstrated PAM effects on the rat M3 receptor in cell assays, and augmented cholinergic bladder contractions both in vivo and in vitro. ASP8302 improved voiding efficiency and reduced residual urine volume in two voiding dysfunction models as effectively as distigmine bromide, but unlike distigmine bromide did not affect the number of stools or tracheal insufflation pressure.

Conclusions: Our results in rats indicate that ASP8302 improves voiding dysfunction by potentiating bladder contraction with fewer effects on cholinergic responses in other organs, and suggest a potential advantage over current cholinomimetic drugs for treating micturition disorders caused by insufficient bladder contraction.

Muscarinic M3阳性变构调节剂ASP8302增强大鼠膀胱收缩,改善排尿功能障碍。
目的:Muscarinic M3 (M3)受体介导膀胱胆碱能平滑肌收缩。目前针对膀胱M3受体治疗排尿障碍的药物由于受体的过度激活和选择性不足,存在胆碱能副作用的风险。我们研究了一种新型M3受体正变构调节剂ASP8302对大鼠膀胱功能的影响。方法:在表达大鼠毒蕈碱受体的细胞中,评估了碳水化合物诱导的细胞内Ca2+增加的调节。用离体大鼠膀胱条和测量麻醉大鼠膀胱内压力来评估膀胱收缩的增强。采用有意识造尿法观察α1 -肾上腺素能受体激动剂米多卡因和毒碱受体拮抗剂阿托品致大鼠排尿功能障碍模型及膀胱出口梗阻对残尿量和排尿效率的影响。为了评估潜在的副作用,分别测量了清醒大鼠和麻醉大鼠的粪便数量和气管充气压力。结果:ASP8302在细胞实验中对大鼠M3受体显示PAM作用,并在体内和体外增强胆碱能膀胱收缩。ASP8302在两种排尿功能障碍模型中提高排尿效率和减少残余尿量的效果与溴异丁胺相同,但与溴异丁胺不同的是,它不影响排便次数或气管充气压力。结论:我们的大鼠实验结果表明,ASP8302通过增强膀胱收缩改善排尿功能障碍,而对其他器官胆碱能反应的影响较小,这表明在治疗膀胱收缩不足引起的排尿障碍方面,ASP8302比目前的拟胆碱药物有潜在的优势。
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来源期刊
LUTS: Lower Urinary Tract Symptoms
LUTS: Lower Urinary Tract Symptoms UROLOGY & NEPHROLOGY-
CiteScore
3.00
自引率
7.70%
发文量
52
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.
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