BLADDER HYPERACTIVITY AFTER OBSTRUCTION RELIEF

每年前列腺素引起的膀胱梗阻， 400，000例手术，占2009年第二大支出， 医疗保险的钱。虽然梗阻在女性中并不常见，但它可能导致 尿失禁手术的病人尽管这种情况普遍存在， 由于持续的紧迫性， 至少有1/3的患者发生频率和排尿困难。部分尿道 大鼠中的结扎代表了这种膀胱活动过度的模型。 虽然尿动力学参数恢复到通畅的水平后， 结扎后1/3 ~ 1/2大鼠尿频持续。生肌和 神经源性假说已经提出来解释的发展， 尿频、尿急和排尿困难伴梗阻增加。 我们 提出梗阻缓解后刺激性排尿导致 平滑肌和/或神经的持续紊乱。已经 表明膀胱平滑肌的阻塞性变化被传递到 神经生长因子（Nerve Growth Factor，NGF）生产的NGF 肥大的平滑肌与 排尿过度活跃这一提议检验了这样一个假设， 去结扎（通畅）大鼠的排尿频率依赖于 逼尿肌平滑肌和/或其神经支配的改变。这 假设将在患有多动症和正常多动症的去结扎大鼠中进行测试。 通过以下方式排泄：1）评价平滑肌对以下物质的体内反应： 卡巴胆碱和膀胱神经元对辣椒素或阿扑吗啡的反应。2)确定 无论是平滑肌含量的变化还是收缩性神经元大小的变化， GAP-43在骶髓中的表达，脊髓反射，NGF含量 在膀胱或神经节中。或NGF受体（p75/trkA）表达相关 与排尿频率，和3）注意，如果酪氨酸激酶抑制剂， 阻断NGF与trkA受体结合的作用， 神经可塑性和尿频。平滑肌肌球蛋白和肌动蛋白 将使用2-D凝胶电泳测量含量。体外肌肉 对胆碱能/嘌呤能激动剂、KCl和电场的浴反应 刺激将评估平滑肌收缩性。体内清醒 对卡巴胆碱、膀胱内辣椒素或 阿扑吗啡将评估平滑肌、传入和中枢机制。 感觉和运动神经元区，GAP-43在骶髓中的表达 排尿反射的电生理特性将提供 了解膀胱反射的结构和功能变化 通路在具有排尿过度活跃的去结扎大鼠中持续存在。 的影响 培养的膀胱平滑肌和骨盆神经元上的TRK抑制剂将 解决药物作用的潜在体内位点。检查能力， 阻塞大鼠逆转阻塞诱导的平滑肌和神经 取消登记后的变化将使人们深入了解 排尿过度活跃 抑制NGF产生或阻断NGF分泌的试剂的用途 它的行动将进一步验证这一假设，并提供一个潜在的 未来临床试验的框架。

Each year obstruction of the urinary bladder from prostatism leads to 400,000 surgeries and accounts for the second largest expenditure of Medicare dollars. Although obstruction is unusual in women it can result from surgery for urinary incontinence. Despite the prevalence of this condition and the costs treatment failures due to persistent urgency, frequency and nocturia occur in at least 1/3 of patients. Partial urethral ligation in the rat represents a model for this bladder hyperactivity. Although urodynamic parameters return to unobstructed levels after deligation, urinary frequency persists in 1/3 to 1/2 of rats. Myogenic and neurogenic hypotheses have been put forth to explain the development of increased urinary frequency urgency and nocturia with obstruction. We propose that irritative voiding following relief of obstruction results from persistent derangements in smooth muscle and/or nerve. it has been shown that obstructive changes in bladder smooth muscle are transmitted to its innervation by Nerve Growth Factor (NGF). NGF produced by hypertrophied smooth muscle has been linked to the development of hyperactive voiding. This proposal tests the hypothesis that resolution of urinary frequency in deligated (unobstructed) rats relies on reversal of alterations in detrusor smooth muscle and/or its innervation. This hypothesis will be tested in deligated rats with hyperactive and normal voiding by: 1) evaluating the in vivo responses of smooth muscle to carbachol, and bladder neurons to capsaicin or apomorphine. 2) determining whether changes in smooth muscle content or contractility neuronal size, GAP-43 expression in the sacral spinal cord, a spinal reflex, NGF content in the bladder or ganglia. or NGF receptor (p75/trkA) expression correlate with voiding frequency, and 3) noting if tyrosine kinase inhibitors that block the effects of NGF binding to the trkA receptor prevent myogenic or neural plasticity and urinary frequency. Smooth muscle myosin and actin content will be measured using 2-D gel electrophoresis. In vitro muscle bath responses to cholinergic/purinergic agonists,' KCl and field stimulation will assess smooth muscle contractility. In vivo awake cystometric and voiding responses to carbachol, intravesical capsaicin or apomorphine will assess smooth muscle, afferent and central mechanisms. Sensory and motoneuron areas, GAP-43 expression in the sacral spinal cord and electrophysiological properties of micturition reflexes will provide insight into whether structural and functional changes in bladder reflex pathways persist in deligated rats with hyperactive voiding. Effects of trk inhibitors on cultured bladder smooth muscle and pelvic neurons will address potential in vivo sites of drug action. Examining the ability, of obstructed rats to reverse obstruction-induced smooth muscle and neural changes after deligation will provide insight into the mechanisms for hyperactive voiding. The use of agents to inhibit NGF production or block its action will further test the hypothesis and offer a potential framework for future clinical trials.