Neurophysiology and Biomechanics of Urethra in SUI

描述（由申请人提供）：压力性尿失禁（SUI）被定义为在没有膀胱收缩的情况下，打喷嚏、咳嗽或大笑时继发于腹部压力增加的非自愿尿失禁。这种疾病是一种重要的妇科/泌尿系统问题，目前影响着大约2500万美国女性。这些SUI患者表现出高发生率的内禀括约肌缺陷，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相关的尿道失禁机制的正常生理和病理生理尚不清楚。因此，利用我们实验室开发的体内和离体技术，我们建议对应激条件下尿道失禁机制进行系统分析。首先，在正常动物和SUI动物模型中进行体内神经生理分析。接下来，将对正常尿道和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的潜在药物治疗方法。在这个提议中，我们假设：1)在正常大鼠的尿道不同位置可以识别出导致正常尿道失禁机制的详细神经生理和生物力学特性；2)在两种不同的SUI动物模型中可以识别出导致尿道失禁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/或肾上腺素受体激动剂的药物治疗可以改善两种SUL动物模型的尿道失禁机制。本资助的具体目的是：1)通过以下方法表征正常动物尿道关闭机制的正常生理和生物力学特性：A)微针尖传感器导管在体内测量打喷嚏或被动增加膀胱内压力时膀胱和尿道的反应，b)在体内测量打喷嚏或被动增加膀胱内压力时泄漏点压力，c)体外全尿道生物力学研究；II)观察两种SUI大鼠模型（阴道过胀或尿道外括约肌及盆底肌神经横断）上述指标的病理变化；III)探讨改善两种SUI大鼠模型尿道关闭机制的可能药物治疗方法。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破坏性疾病的希望。这被认为是SUI患者泌尿/妇科护理的重中之重。

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.