PDF(Pubmed)
Abstract：
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.
摘要：
硬度和顺应性之间的平衡对于正常的膀胱功能至关重要，和膀胱壁的机械性能的变化发生在许多膀胱病变中。这些变化通常与碱性促分泌素的释放有关，而碱性促分泌素的释放又驱动炎症介质从肥大细胞的释放。通过基本促分泌素的肥大细胞脱颗粒被认为是通过激活孤儿受体而发生的。Mas相关G蛋白偶联受体B2(Mrgprb2)。我们探索了假定的肥大细胞去粒剂和Mrgprb2激动剂化合物48/80对膀胱壁机械顺应性的影响，平滑肌收缩性，和尿动力学，如果这些效应是肥大细胞依赖性的。在野生型小鼠中,Mrgprb2受体mRNA在尿路上皮和平滑肌层中均有表达。膀胱内滴注化合物48/80减少了排尿间隔和空隙体积，表明膀胱过度活动。化合物48/80还增加了膀胱顺应性,同时增加了离体充盈期间瞬时压力事件的幅度和前导斜率,并且这些作用被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，表明这些作用与肥大细胞无关。这些发现表明化合物48/80降解细胞外基质并通过激活位于肥大细胞外部的Mrgprb2受体增加膀胱平滑肌兴奋性。因此，Mrgprb2在膀胱中的药理学和生理学在治疗下尿路功能障碍方面具有潜在的兴趣和重要性。
