Analysis of urinary dysfunction and drug discovery by in vivo measurement of drug-receptor binding

本研究的目的是表征脑梗死、慢性膀胱出口梗阻、环磷酰胺（CTX）和盐酸处理的大鼠作为良性前列腺增生（BPH）引起的排尿功能障碍模型的膀胱神经递质受体结合和尿动力学参数，膀胱过度活动症（OAB）和间质性膀胱炎（IC）。1）膀胱容量和排尿量在脑-比假手术大鼠梗死。膀胱出口梗阻大鼠排尿前出现不自主收缩，而假手术大鼠则无。脑梗死大鼠膀胱M受体表达上调，而非膀胱出口梗阻大鼠，脑梗死后逼尿肌功能亢进的症状可能与M受体表达上调有关。2）CYP治疗组大鼠膀胱测压结果显示，与对照组相比，大鼠排尿时间和排尿量明显延长，排尿时间和排尿量明显减少。 关于我们 排尿次数和基础压明显增加。尿动力学参数的这些变化可能是CYP处理大鼠逼尿肌过度活动的特征。因此，已经显示，顺铂治疗引起大鼠膀胱中顺铂相关受体的下调。本研究提供了进一步的药理学证据表明，毒蕈碱和嘌呤能机制都显着有助于由于IC的排尿功能障碍。3）血管紧张素II（Ang II）受体显着上调大鼠膀胱由于膀胱出口梗阻。在大鼠中重复经口给予替米沙坦可完全阻止膀胱出口梗阻诱导的膀胱血管紧张素II受体上调的发生。替米沙坦治疗还有效地减弱了由尿路梗阻引起的膀胱湿重增加。因此，膀胱血管紧张素Ⅱ可能至少部分与膀胱出口梗阻后发生的泌尿功能障碍的发病机制有关，本研究提出了膀胱血管紧张素相关受体的激动剂或拮抗剂是治疗泌尿功能障碍的有用药物的可能性。少

The aim of this study is to characterize bladder neurotransmitter receptor binding and urodynamic parameters in rats with cerebral infarction, chronic bladder outlet obstruction, cyclophosphamide (CYP) and HCl-treated rats as models of urinary dysfunction due to benign prostatic hyperplasia (BPH) , overactive bladder (OAB) and interstitial cystitis (IC).1) Bladder capacity and voided volume were significantly lower in the cerebral-infarcted than in the sham rats. Involuntary contractions before micturition were seen in the bladder outlet-obstructed rats but not in sham rats. The cerebral infarction but not bladder outlet obstruction in rats caused up-regulation of bladder muscarinic receptors, and that such regulation of bladder muscarinic receptors may be at least partly associated with the symptoms of detrusor overactivity subsequent to cerebral infarction.2) In the cystometry of CYP-treated rats compared with control rats, the micturition interval and micturition volume were signifi … More cantly decreased and the frequency of micturition and basal pressure were significantly increased. These changes in urodynamic parameters may characterize the detrusor overactivity occurring in CYP-treated rats. Thus, CYP treatment has been shown to cause down-regulation of pharmacologically relevant receptors in the bladder of rats. The present study offers further pharmacological evidence that both muscarinic and purinergic mechanisms contribute significantly to the urinary dysfunction due to IC.3) The angiotensin II (Ang II) receptor was significantly up-regulated in the rat bladder due to the bladder outlet obstruction. Repeated oral administration of telmisartan in rats completely prevented the development of a bladder outlet obstruction-induced up-regulation of bladder Ang II receptors. Telmisartan treatment also effectively attenuated the increase in bladder wet weight caused by urinary outlet obstruction. Thus, bladder Ang II may be at least partly associated with the pathogenesis of urinary dysfunction occurring subsequent to bladder outlet obstruction.The present study raise the possibility that agonists or antagonists of pharmacologically relevant receptors in the bladder is a useful therapeutic drug for the treatment of urinary dysfunction. Less