Compound 48/80 increases murine bladder wall compliance independent of mast cells.
Compound 48/80 increases murine bladder wall compliance independent of mast cells.
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DOI：
10.1038/s41598-023-27897-6
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发表时间：
2023-01-12
影响因子：
4.6
通讯作者：
Tykocki NR
中科院分区：
文献类型：
--
作者：
Saxena P;Broemer E;Herrera GM;Mingin GC;Roccabianca S;Tykocki NR
硬度和顺应性之间的平衡对于正常的膀胱功能至关重要，并且膀胱壁的机械特性的变化发生在许多膀胱病理中。这些变化通常与基本促分泌素的释放有关，而促分泌素反过来又驱动肥大细胞释放炎症介质。碱性促分泌剂引起的肥大细胞脱颗粒被认为是通过激活孤儿受体 Mas 相关 G 蛋白偶联受体 B2 (Mrgprb2) 来发生的。我们探讨了假定的肥大细胞脱粒剂和 Mrgprb2 激动剂化合物 48/80 对膀胱壁机械顺应性、平滑肌收缩性和尿动力学的影响，以及这些影响是否依赖于肥大细胞。在野生型小鼠中，Mrgprb2 受体 mRNA 在尿路上皮和平滑肌层中表达。化合物48/80的膀胱内滴注减少了间尿间隔和排尿量，表明膀胱过度活动。化合物48/80还增加膀胱顺应性，同时增加离体充盈过程中瞬时压力事件的幅度和前导斜率，并且这些效应被Mrgprb2拮抗剂QWF抑制。令人惊讶的是，化合物48/80的所有作用在肥大细胞缺陷小鼠中持续存在，表明这些作用独立于肥大细胞。这些发现表明，化合物 48/80 通过激活位于肥大细胞外部的 Mrgprb2 受体来降解细胞外基质并增加膀胱平滑肌的兴奋性。因此，Mrgprb2在膀胱中的药理学和生理学对于治疗下尿路功能障碍具有潜在的兴趣和重要性。
A balance between stiffness and compliance is essential to normal bladder function, and changes in the mechanical properties of the bladder wall occur in many bladder pathologies. These changes are often associated with the release of basic secretagogues that in turn drive the release of inflammatory mediators from mast cells. Mast cell degranulation by basic secretagogues is thought to occur by activating an orphan receptor, Mas-related G protein-coupled receptor B2 (Mrgprb2). We explored the effects of the putative mast cell degranulator and Mrgprb2 agonist Compound 48/80 on urinary bladder wall mechanical compliance, smooth muscle contractility, and urodynamics, and if these effects were mast cell dependent. In wild-type mice, Mrgprb2 receptor mRNA was expressed in both the urothelium and smooth muscle layers. Intravesical instillation of Compound 48/80 decreased intermicturition interval and void volume, indicative of bladder overactivity. Compound 48/80 also increased bladder compliance while simultaneously increasing the amplitude and leading slope of transient pressure events during ex vivo filling and these effects were inhibited by the Mrgprb2 antagonist QWF. Surprisingly, all effects of Compound 48/80 persisted in mast cell-deficient mice, suggesting these effects were independent of mast cells. These findings suggest that Compound 48/80 degrades extracellular matrix and increases urinary bladder smooth muscle excitability through activation of Mrgprb2 receptors located outside of mast cells. Thus, the pharmacology and physiology of Mrgprb2 in the urinary bladder is of potential interest and importance in terms of treating lower urinary tract dysfunction.
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影响因子：
4.5
作者：
Drake MJ;Kanai A;Bijos DA;Ikeda Y;Zabbarova I;Vahabi B;Fry CH
通讯作者：
Fry CH
影响因子：
7.3
作者：
Dondalska A;Rönnberg E;Ma H;Pålsson SA;Magnusdottir E;Gao T;Adam L;Lerner EA;Nilsson G;Lagerström M;Spetz AL
通讯作者：
Spetz AL
影响因子：
2.7
作者：
Fitzgerald, Jocelyn J.;Ustinova, Elena;Koronowski, Kevin B.;de Groat, William C.;Pezzone, Michael A.
通讯作者：
Pezzone, Michael A.
DOI：
10.1016/j.jaci.2016.12.980
发表时间：
2017-08
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Azimi E;Reddy VB;Pereira PJS;Talbot S;Woolf CJ;Lerner EA
通讯作者：
Lerner EA
影响因子：
7.8
作者：
HINEK, A;RABINOVITCH, M
通讯作者：
RABINOVITCH, M