Department of Pharmacology, University of Vermont, Burlington, Vermont, United States.
Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
Am J Physiol Regul Integr Comp Physiol. 2024 Jul 1;327(1):R97-R108. doi: 10.1152/ajpregu.00084.2024. Epub 2024 May 23.
The transitional epithelial cells (urothelium) that line the lumen of the urinary bladder form a barrier between potentially harmful pathogens, toxins, and other bladder contents and the inner layers of the bladder wall. The urothelium, however, is not simply a passive barrier, as it can produce signaling factors, such as ATP, nitric oxide, prostaglandins, and other prostanoids, that can modulate bladder function. We investigated whether substances produced by the urothelium could directly modulate the contractility of the underlying urinary bladder smooth muscle. Force was measured in isolated strips of mouse urinary bladder with the urothelium intact or denuded. Bladder strips developed spontaneous tone and phasic contractions. In urothelium-intact strips, basal tone, as well as the frequency and amplitude of phasic contractions, were 25%, 32%, and 338% higher than in urothelium-denuded strips, respectively. Basal tone and phasic contractility in urothelium-intact bladder strips were abolished by the cyclooxygenase (COX) inhibitor indomethacin (10 µM) or the voltage-dependent Ca channel blocker diltiazem (50 µM), whereas blocking neuronal sodium channels with tetrodotoxin (1 µM) had no effect. These results suggest that prostanoids produced in the urothelium enhance smooth muscle tone and phasic contractions by activating voltage-dependent Ca channels in the underlying bladder smooth muscle. We went on to demonstrate that blocking COX inhibits the generation of transient pressure events in isolated pressurized bladders and greatly attenuates the afferent nerve activity during bladder filling, suggesting that urothelial prostanoids may also play a role in sensory nerve signaling. This paper provides evidence for the role of urothelial-derived prostanoids in maintaining tone in the urinary bladder during bladder filling, not only underscoring the role of the urothelium as more than a barrier but also contributing to active regulation of the urinary bladder. Furthermore, cyclooxygenase products greatly augment sensory nerve activity generated by bladder afferents during bladder filling and thus may play a role in perception of bladder fullness.
衬于膀胱腔的移行上皮细胞（尿路上皮）形成了一道屏障，使潜在的有害病原体、毒素和其他膀胱内容物与膀胱壁的内层隔开。然而，尿路上皮并不仅仅是一个被动的屏障，因为它可以产生信号因子，如 ATP、一氧化氮、前列腺素和其他前列腺素，从而调节膀胱功能。我们研究了尿路上皮产生的物质是否可以直接调节下尿路平滑肌的收缩性。通过在保留或去除尿路上皮的情况下，对分离的小鼠膀胱条带进行力的测量。膀胱条带自发形成张力和时相收缩。在保留尿路上皮的条带中，基础张力以及时相收缩的频率和幅度分别比去除尿路上皮的条带高 25%、32%和 338%。在保留尿路上皮的膀胱条带中，基础张力和时相收缩性被环氧化酶（COX）抑制剂吲哚美辛（10 µM）或电压依赖性钙通道阻滞剂地尔硫卓（50 µM）所消除，而用河豚毒素（1 µM）阻断神经元钠离子通道则没有效果。这些结果表明，尿路上皮产生的前列腺素通过激活下尿路平滑肌中的电压依赖性钙通道，增强了平滑肌的张力和时相收缩。我们进一步证明，阻断 COX 抑制了在分离的加压膀胱中瞬态压力事件的产生，并大大减弱了在膀胱充盈期间传入神经活动，这表明尿路上皮前列腺素也可能在感觉神经信号传导中发挥作用。本文提供了尿路上皮衍生的前列腺素在膀胱充盈期间维持膀胱张力的作用的证据，不仅强调了尿路上皮不仅仅是一个屏障的作用，而且有助于对膀胱的主动调节。此外，环氧化酶产物大大增加了膀胱传入神经在膀胱充盈期间产生的神经活动，因此可能在感知膀胱充盈方面发挥作用。
