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Neurophysiology and Biomechanics of Urethra in Stress Urinary Incontinence

压力性尿失禁尿道的神经生理学和生物力学

基本信息

批准号：
7228532
负责人：
NAOKI YOSHIMURA
金额：
$ 32.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228532
关键词：
Adrenergic Agonists Adrenergic Antagonists Adrenergic Receptor Adult Affect Age Age-Years Agonist American Anatomy Animal Model Animals Anterior nares Appendix Bilateral Biomechanics Birth trauma Bladder Bladder Control Blood Vessels Bungarotoxins C Fiber Calcitonin Gene-Related Peptide Caliber Capsaicin Caring Catheters Classification Clinical Clinical Research Closure Collagen Condition Connective Tissue Coughing Denervation Disease Dose Drug effect disorder Elastin Electromyography Elevation Environment Estrogens Etiology Event Exhibits Female Fiber Fibers, A Fluoxetine Functional disorder Ganglionic Blockers Grant Gynecologic Harvest Hexamethonium Incidence Incontinence Individual Injury Intravenous Investigation Laboratories Length Measurable Measurement Measures Mechanics Mediating Menopause Methods Modality Modeling Muscle Muscle Fibers Nerve Nerve Degeneration Neurologic Neuromuscular Blocking Agents Neurons Neuropathy Neuropeptides Neurotoxins Nitric Oxide Donors Norepinephrine Numbers Operative Surgical Procedures Pathologic Pathology Pathway interactions Patients Pelvic Floor Muscle Pelvic floor structure Pelvis Perfusion Peripheral Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Physiological Physiology Positioning Attribute Prazosin Prevention Principal Investigator Process Property Rattus Reflex action Resistance Role Route SKI gene Secondary to Simulate Site Smooth Muscle Sneezing Sphincter Spinal Stress Stress Urinary Incontinence Striated Muscles Surface System Techniques Therapeutic Effect Thinking Time Tissues Transducers Urethra Urethral sphincter Urinary Incontinence Urine Vagina Vibrissae Week Woman Work abdominal pressure base day design duloxetine improved in vivo inhibitor/antagonist interdisciplinary approach intravesical nerve injury nerve supply neurofilament neurophysiology nisoxetine older women parity polypeptide C pressure prevent programs research study response reuptake size transmission process urologic

项目摘要

DESCRIPTION (provided by applicant): Stress urinary incontinence (SUI) is defined as involuntary loss of urine secondary to an increase in abdominal pressure during events such as sneezing, coughing or laughing in the absence of bladder contractions. This disorder is a significant gynecological/urological problem currently affecting approximately 25 million American women. These SUI patients exhibit the high incidence of intrinsic sphincter deficiency, characterized by a malfunction of the urethral sphincter mechanism resulting in the low-pressure urethra. However, normal physiology and pathophysiology of the urethral continence mechanism in relation to SUI are not well elucidated. Thus, utilizing both in-vivo and ex-vivo techniques developed in our laboratory, we propose to perform systematic analyses of urethral continence mechanisms under stress conditions. First, in-vivo neurophysiological analyses will be performed in normal animals and animal models of SUI. Next, ex-vivo biomechanical analyses will be performed of the normal and SUI urethra. Finally, based on these results, we will also seek to explore potential pharmacotherapies of SUI. In this proposal, we hypothesize: 1) the detailed neurophysiological and biomechanical properties contributing to normal urethral continence mechanisms at different positions along the urethra can be identified in normal rats, 2) pathological changes in neurophysiological and biomechanical properties of urethral continence mechanisms can be identified in two different animals models of SUI, and 3) pharmacological treatments using serotonine/norepinephrine reuptake inhibitors and/or adrenoceptor agonists can improve urethral continence mechanisms in two animal models of SUL The Specific Aims of this grant are: I) to characterize the normal physiological and biomechanical properties of the urethral closure mechanisms in normal animals using: a) microtip transducer catheters to measure bladder and urethral responses in-vivo during sneezing or passive increases in intravesical pressure, b) in-vivo leak point pressure measurements during sneezing or passive increases in intravesical pressure, and c) ex-vivo whole urethra biomechanical studies; II) to investigate the pathological changes in the above measurements in two rat models of SUI (vaginal over distension or transection of the nerves to external urethral sphincter and pelvic floor muscles); and III) to investigate possible pharmacotherapies for improving the urethral closure mechanism in the two rat models of SUI. By defining the detailed urethral pathology of SUI, we can offer the hope of prevention and reversal of this potentially devastating condition. This is recognized as a high priority in the urologic/gynecologic care of SUI patients.

描述(申请人提供)：压力性尿失禁(SUI)被定义为在没有膀胱收缩的情况下，在打喷嚏、咳嗽或大笑等事件中继发于腹压增加而导致的非自愿尿失禁。这种疾病是一个严重的妇科/泌尿科问题，目前影响着大约2500万美国妇女。这些SUI患者表现出固有括约肌缺陷的高发生率，其特征是尿道括约肌机制故障导致尿路低压。然而，与SUI相关的正常生理学和病理生理学关于尿路失禁的机制还没有很好的阐明。因此，利用我们实验室开发的体内和体外技术，我们建议对应激条件下的尿路控制机制进行系统的分析。首先，将在正常动物和SUI动物模型中进行体内神经生理学分析。接下来，我们将对正常和SUI的尿路进行体外生物力学分析。最后，基于这些结果，我们还将寻求SUI潜在的药物治疗方法。在这个方案中，我们假设：1)在正常大鼠的尿路不同位置，可以确定与正常尿路控制机制有关的详细的神经生理和生物力学特性；2)在两种不同的SUI动物模型中，可以确定尿路可控机制的神经生理和生物力学特性的病理变化，3)使用5-羟色胺/去甲肾上腺素再摄取抑制剂和/或肾上腺素能受体激动剂的药物治疗可以改善SUL两种动物模型的尿路控制机制。这项资助的具体目的是：1)研究正常动物尿路关闭机制的正常生理和生物力学特性：a)微尖换能器导管用于测量打喷嚏或膀胱内压力被动升高时体内的膀胱和尿路反应，b)体内打喷嚏或膀胱内压力被动升高时漏点压力的测量，以及c)体外整体尿路生物力学研究；Ii)研究两种SUI模型(阴道过度扩张或切断支配外括约肌和盆底肌的神经)上述指标的病理变化；iii)探讨改善两种SUI模型大鼠尿路闭合机制的可能药物疗法。通过明确SUI的详细的尿路病理，我们可以提供预防和逆转这种潜在的破坏性疾病的希望。这在SUI患者的泌尿/妇科护理中被认为是高度优先的。