ROLE OF NITRIC OXIDE IN INTERSTITIAL CYSTITIS

描述(摘自申请者的摘要)：最近的证据表明 膀胱内传入细胞或上皮细胞的改变可以 导致神经兴奋性的改变，这可能是脑出血的部分原因 间质性膀胱炎(IC)。IC是一种原因不明的慢性临床综合征 并表现出各种复杂的感官症状。这可能涉及到 传入神经元的原发缺陷或其周围环境的改变。 初步数据表明，猫体内的IC可以改变化学物质的释放 来自传入神经的介质(一氧化氮，NO；ATP)以及 尿路上皮炎。有研究表明，化学物质的释放变化可能会影响 通过增加传入兴奋性和尿路上皮膜功能 对有毒物质的渗透性。这些数据增加了一种可能性 尿路上皮参与了膀胱的细胞间信号传递。 神经-上皮相互作用可以调节膀胱功能。建议数 实验将使用新的方法，如培养的尿路上皮细胞和 选择性一氧化氮卟啉微传感器在自然发生的动物模型中的应用 IC(猫间质性膀胱炎)，已被证明有许多 与人类的IC相似，以检验化学和/或 血管内皮细胞或传入细胞内信号转导机制 IC中的膀胱发生改变。自然发生的IC而不是急性的 健康动物的膀胱损伤或炎症模型允许更相关 IC的病理生理学研究。目标#1将评估以下特征 正常猫和IC猫的尿路上皮。接下来是传入神经的位置 提示尿路上皮细胞可能是 从膀胱神经释放的递质或由上皮细胞释放的递质 可以改变传入神经元的兴奋性。Aim#2将评估 正常和IC猫膀胱传入神经的特点。我们会 评估正常膀胱传入神经的特性以确定如何传入 可以在IC中更改。这些研究可能导致选择性的药理学 针对神经上皮细胞释放或信号缺陷的干预措施 为临床和病理生理研究提供了新的前景。 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.