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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（由申请人提供）：压力性尿失禁（SUI）定义为在没有膀胱收缩的情况下，在打喷嚏、咳嗽或大笑等事件期间，继发于腹压升高的不自主尿液丢失。这种疾病是一个重要的妇科/泌尿系统问题，目前影响着大约2500万美国妇女。这些SUI患者表现出高发病率的内在括约肌缺陷，其特征是尿道括约肌机制的功能障碍，导致尿道低压。然而，与SUI相关的尿道扩张机制的正常生理学和病理生理学尚未得到很好的阐明。因此，利用我们实验室开发的体内和体外技术，我们建议在压力条件下对尿道扩张机制进行系统分析。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，将对正常和SUI尿道进行离体生物力学分析。最后，基于这些结果，我们还将寻求探索SUI的潜在药物治疗。在本提案中，我们假设：1）可以在正常大鼠中鉴定在沿着尿道的沿着不同位置处有助于正常尿道扩张机制的详细神经生理学和生物力学性质，2）可以在两种不同的SUI动物模型中鉴定尿道扩张机制的神经生理学和生物力学性质的病理变化，和3）使用肾上腺素/去甲肾上腺素再摄取抑制剂和/或肾上腺素受体激动剂的药物治疗可以改善两种SUL动物模型的尿道扩张机制。I）使用以下方法表征正常动物中尿道闭合机制的正常生理和生物力学特性：a）微尖端传感器导管，用于在打喷嚏或膀胱内压力被动增加期间测量体内膀胱和尿道反应，B）在打喷嚏或膀胱内压力被动增加期间的体内泄漏点压力测量，和c）离体全尿道生物力学研究; II）在两种SUI大鼠模型中研究上述测量的病理变化（阴道过度扩张或切断尿道外括约肌和盆底肌肉的神经）;和III）研究改善两种SUI大鼠模型中尿道闭合机制的可能药物疗法。通过定义SUI的详细尿道病理，我们可以提供预防和逆转这种潜在的破坏性疾病的希望。这被认为是SUI患者泌尿/妇科护理的高度优先事项。