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

本研究旨在研究脑梗死、慢性膀胱出口梗阻、环磷酰胺（CYP）和盐酸处理大鼠作为良性前列腺增生（BPH）、膀胱过度活动（OAB）和间质性膀胱炎（IC）所致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。1)脑梗死大鼠膀胱容量和排空体积明显低于假手术大鼠。膀胱出口阻塞大鼠排尿前出现不自主收缩，而假手术大鼠排尿前无不自主收缩。大鼠脑梗死而非膀胱出口梗阻引起膀胱毒蕈碱受体的上调，这种膀胱毒蕈碱受体的上调可能与脑梗死后逼尿肌过度活动的症状至少部分相关。2)与对照大鼠相比，cyp治疗大鼠的排尿间隔和排尿量明显缩短，排尿频率和基础压明显升高。这些尿动力学参数的变化可能表征了cypp治疗大鼠的逼尿肌过度活动。因此，CYP治疗已被证明可引起大鼠膀胱中药理学相关受体的下调。本研究提供了进一步的药理学证据，表明毒蕈碱和嘌呤能两种机制在ic引起的尿功能障碍中都起着重要的作用。3)膀胱出口梗阻导致大鼠膀胱血管紧张素II （Ang II）受体显著上调。大鼠反复口服替米沙坦完全阻止膀胱出口阻塞引起的膀胱Ang II受体上调的发生。替米沙坦治疗还能有效减轻尿出口梗阻引起的膀胱湿重增加。因此，膀胱Ang II可能至少部分与膀胱出口梗阻后发生的尿功能障碍的发病机制有关。本研究提出膀胱中药理学相关受体的激动剂或拮抗剂可能是治疗泌尿功能障碍的有效治疗药物。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