BLADDER HYPERACTIVITY AFTER OBSTRUCTION RELIEF

每年前列腺癌引起的膀胱梗阻都会导致 400,000例手术，占第二大支出 医疗保险美元。尽管梗阻在女性中很少见，但它可能会导致 因为大小便失禁而做手术。尽管这种情况很普遍 由于持续的紧急情况而导致的治疗失败的状况和成本， 至少1/3的患者会出现尿频和夜尿。部分尿路 大鼠的结扎是这种膀胱过度活动的一种模型。 尽管尿流动力学参数在术后恢复到通畅水平 结扎后，1/3~1/2的大鼠尿频持续存在。肌源性和 已经提出了神经源性假说来解释脑血管疾病的发展 尿频增加、紧迫感和夜间尿流梗阻。我们 建议在解除梗阻后进行刺激性排尿 由平滑肌和/或神经的持续性排列紊乱引起。一直以来都是这样 显示梗阻性改变的膀胱平滑肌传导至 神经生长因子(NGF)对其进行神经支配。NGF由 肥大的平滑肌与高血压的发生有关。 排尿过度活跃。这一提议检验了这样一个假设，即解决 结扎(通畅)大鼠的尿频依赖于 逼尿肌平滑肌和/或其神经支配的改变。这 假说将在多动和正常的结扎大鼠身上进行检验 排尿方法：1)评价血管内皮细胞对 卡巴胆碱、膀胱神经元对辣椒素或阿朴吗啡有抑制作用。2)确定 无论是平滑肌含量的变化还是收缩能力神经元大小的变化， 生长相关蛋白-43在脊髓中的表达、脊髓反射、神经生长因子含量 在膀胱或神经节内。或NGF受体(p75/TrkA)表达相关 排尿频率，以及3)注意酪氨酸激酶抑制剂是否 阻断NGF与TrkA受体结合的作用可预防肌源性高血压 神经可塑性和尿频。平滑肌肌球蛋白与肌动蛋白 含量将使用二维凝胶电泳法进行测量。体外肌肉 对胆碱能/嘌呤能激动剂、KCl和FIELD的洗浴反应 刺激将评估平滑肌的收缩能力。活体清醒 卡巴胆碱、膀胱内辣椒素或 阿朴吗啡将评估平滑肌、传入和中枢机制。 感觉区和运动神经元GAP-43在脊髓中的表达 排尿反射的电生理特性将提供 对膀胱反射的结构和功能改变是否有洞察 在排尿过度活跃的结扎大鼠身上，这些通路仍然存在。的效果 Trk抑制剂对培养的膀胱平滑肌和盆腔神经元的影响 解决体内潜在的药物作用部位。检查能力， 梗阻大鼠逆转梗阻诱导的血管和神经 隔离后的变化将提供对以下机制的见解 排尿过度活跃。使用药物来抑制NGF的产生或阻断 它的行动将进一步检验这一假设，并提供潜在的 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.