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BLADDER HYPERACTIVITY AFTER OBSTRUCTION RELIEF

梗阻缓解后膀胱过度活跃

基本信息

批准号：
2905867
负责人：
WILLIAM DONALD STEERS
金额：
$ 15.95万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2000-04-30
项目状态：
已结题

项目摘要

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.

每年前列腺炎引起的膀胱梗阻都会导致 40万例手术，占第二大支出医疗保险美元。尽管阻塞在女性中并不常见，但它可能会导致因尿失禁手术。尽管这种现象普遍存在由于持续的紧迫性而导致治疗失败的情况和费用，至少1/3的患者出现尿频和夜尿。部分尿道大鼠结扎代表了这种膀胱过度活跃的模型。尽管尿动力学参数在术后恢复到无障碍水平结扎后，1/3至1/2的大鼠持续存在尿频。肌源性和神经源性假说已被提出来解释尿频、尿急、夜尿梗阻增加。我们提出缓解梗阻后出现刺激性排尿来自平滑肌和/或神经的持续紊乱。它一直研究表明，膀胱平滑肌的阻塞性变化会传递到其神经生长因子（NGF）的神经支配。 NGF 产生于肥大的平滑肌与以下疾病的发展有关：排尿过度。该提案测试了以下假设：指定（通畅）大鼠的尿频依赖于逆转逼尿肌平滑肌和/或其神经支配的改变。这假设将在多动和正常的指定大鼠中进行检验排尿通过：1）评估平滑肌的体内反应卡巴胆碱和膀胱神经元转化为辣椒素或阿扑吗啡。 2）确定无论是平滑肌含量或收缩性神经元大小的变化，骶脊髓 GAP-43 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，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，防止肌源性或神经可塑性和尿频。平滑肌肌球蛋白和肌动蛋白将使用二维凝胶电泳测量含量。体外肌肉浴对胆碱能/嘌呤能激动剂、KCl 和场的反应刺激将评估平滑肌收缩力。体内清醒对卡巴胆碱、膀胱内辣椒素或膀胱内辣椒素的膀胱测压和排尿反应阿朴吗啡将评估平滑肌、传入和中枢机制。感觉和运动神经元区域，骶脊髓中的 GAP-43 表达排尿反射的电生理学特性将提供深入了解膀胱反射的结构和功能是否发生变化在排尿过度的大鼠中，该通路仍然存在。的影响培养的膀胱平滑肌和盆腔神经元上的 trk 抑制剂会解决药物作用的潜在体内位点。考察能力，阻塞大鼠逆转阻塞引起的平滑肌和神经委托后的变化将提供对机制的深入了解排尿过度。使用抑制或阻断 NGF 产生的药物其行动将进一步检验假设并提供潜在的未来临床试验的框架。