ROLE OF NITRIC OXIDE IN INTERSTITIAL CYSTITIS

描述（改编自申请人的摘要）：最近的证据表明， 膀胱中传入神经或上皮细胞的改变 导致神经兴奋性的变化，可能是 间质性膀胱炎（IC）。IC是一种病因不明的慢性临床综合征 并表现出各种复杂的感觉症状。这可能涉及 传入神经元的原发性缺陷或其周围环境的变化。 初步数据表明，猫体内的IC可以改变化学物质的释放， 介质（一氧化氮，NO; ATP）从传入神经以及 尿道炎有人认为，改变化学释放可能会影响 传入兴奋性以及尿路上皮膜功能，通过增加 有害物质的渗透性。这些数据提出了一种可能性， 尿道鞘参与膀胱中的细胞间信号传导 并且神经-上皮相互作用可以调节膀胱功能。拟议 实验将使用新的方法，如培养的尿路上皮细胞和 选择性NO卟啉微传感器在自然发生的动物模型， IC（猫间质性膀胱炎），已被证明有许多 与人类IC的相似性，以检查化学和/或 细胞内信号传导机制的传入或上皮细胞在 膀胱改变。自然发生的IC而非急性IC 健康动物的膀胱损伤或炎症模型允许更相关的 IC的病理生理学研究。目标#1将评估以下特征： 正常猫和IC猫的尿道扩张。传入神经的位置 表明尿路上皮细胞可能是 从膀胱神经或上皮细胞释放的递质 可以改变传入神经的兴奋性目标#2将评估 正常猫和IC猫的膀胱传入特性。我们将 评估正常膀胱传入纤维的特性，以确定传入纤维如何 可以在IC中改变。这些研究可能导致选择性药理学 针对神经上皮释放或信号缺陷的干预措施 为进一步研究脑梗死的病理生理和临床提供了新的思路 膀胱疾病的管理。

DESCRIPTION (Adapted from the Applicant's Abstract): Recent evidence suggests that alterations in afferents or epithelial cells in the urinary bladder can lead to changes in neural excitability and may be part of the etiology of interstitial cystitis (IC). IC is a chronic clinical syndrome of unknown cause and presents with varying and complex sensory symptoms. This may involve a primary defect in afferent neurons or a change in their peripheral environment. Preliminary data indicate that IC in cats can alter the release of chemical mediators (nitric oxide, NO; ATP) from afferent nerves as well as the urothelium. It has been suggested that altered chemical release may influence afferent excitability as well as urothelial membrane function, by increasing the permeability to noxious substances. These data raise the possibility that the urothelium is involved in intercellular signaling in the urinary bladder and neural-epithelial interactions can modulate bladder function. The proposed experiments will use new methods such as cultured urothelial cells and a selective NO porphyrinic microsensor in a naturally occurring animal model of IC (feline interstitial cystitis), which has been demonstrated to have many similarities with IC in humans, to examine the hypothesis that chemical and/or intracellular signaling mechanisms in afferent or epithelial cells in the urinary bladder are altered in IC. Naturally occurring IC rather than acute bladder injury or inflammation models in healthy animals permit more relevant studies of pathophysiology of IC. Aim #1 will evaluation the characteristics of the urothelium in both normal and IC cats. The location of afferent nerves next to the urothelium suggests that urothelial cells might be targets for transmitters released from bladder nerves or that release by epithelial cells could alter the excitability of afferents. Aim #2 will evaluate the characteristics of bladder afferents in both normal and IC cats. We will evaluate the properties of normal bladder afferents to determine how afferents can be altered in IC. These studies may lead to selective pharmacologic interventions aimed at targeting neural-epithelial release or signaling defects and could provide a new prospective on the pathophysiology and clinical management of bladder disorders.