{"title":"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。","authors":"Risa Okimoto, Katsutoshi Ino, Kenichiro Ishizu, Hajime Takamatsu, Kazuyuki Sakamoto, Hironori Yuyama, Katsunori Imazumi, Akiyoshi Ohtake, Noriyuki Masuda, Masahiro Takeda","doi":"10.1111/luts.12430","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Muscarinic M<sub>3</sub> (M<sub>3</sub> ) receptors mediate cholinergic smooth muscle contraction of the bladder. Current drugs targeting bladder M<sub>3</sub> 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 M<sub>3</sub> receptors, on bladder function in rats.</p><p><strong>Methods: </strong>Modulation of carbachol-induced increases in intracellular Ca<sup>2+</sup> 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 α<sub>1</sub> -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.</p><p><strong>Results: </strong>ASP8302 demonstrated PAM effects on the rat M<sub>3</sub> 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18028,"journal":{"name":"LUTS: Lower Urinary Tract Symptoms","volume":null,"pages":null},"PeriodicalIF":1.5000,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Muscarinic M<sub>3</sub> positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats.\",\"authors\":\"Risa Okimoto, Katsutoshi Ino, Kenichiro Ishizu, Hajime Takamatsu, Kazuyuki Sakamoto, Hironori Yuyama, Katsunori Imazumi, Akiyoshi Ohtake, Noriyuki Masuda, Masahiro Takeda\",\"doi\":\"10.1111/luts.12430\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>Muscarinic M<sub>3</sub> (M<sub>3</sub> ) receptors mediate cholinergic smooth muscle contraction of the bladder. Current drugs targeting bladder M<sub>3</sub> 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 M<sub>3</sub> receptors, on bladder function in rats.</p><p><strong>Methods: </strong>Modulation of carbachol-induced increases in intracellular Ca<sup>2+</sup> 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 α<sub>1</sub> -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.</p><p><strong>Results: </strong>ASP8302 demonstrated PAM effects on the rat M<sub>3</sub> 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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":18028,\"journal\":{\"name\":\"LUTS: Lower Urinary Tract Symptoms\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2022-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"LUTS: Lower Urinary Tract Symptoms\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/luts.12430\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/2/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"LUTS: Lower Urinary Tract Symptoms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/luts.12430","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/2/12 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
Muscarinic M3 positive allosteric modulator ASP8302 enhances bladder contraction and improves voiding dysfunction in rats.
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.
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.