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

本研究的目的是观察脑梗塞、慢性膀胱出口梗阻、环磷酰胺(CYP)和盐酸治疗的良性前列腺增生症(BPH)、膀胱过度活动症(OAB)和间质性膀胱炎(IC)所致的尿路功能障碍大鼠的膀胱神经递质受体结合和尿动力学参数的变化。膀胱出口阻塞的大鼠在排尿前可见非自主收缩，而假手术大鼠则未见。脑梗塞而不是膀胱出口梗阻引起了大鼠膀胱M受体的上调，这种上调可能至少部分与脑梗塞后逼尿肌过度活动的症状有关。2)与对照组大鼠相比，CYP组大鼠的排尿间期和尿量明显缩短(P<0.0 5)，…排尿次数和基础压明显增加。这些尿动力学参数的变化可能是CYP治疗大鼠逼尿肌过度活动的特征。因此，CYP治疗已被证明导致大鼠膀胱中药物相关受体的下调。本研究提供了进一步的药理学证据，表明毒扁豆碱和嘌呤能机制在ICA所致的尿路功能障碍中起重要作用。3)由于膀胱出口梗阻，血管紧张素II(Ang II)受体在大鼠膀胱中的表达显著上调。大鼠反复口服替米沙坦完全阻止了由膀胱Ang II受体上调引起的膀胱出口梗阻的发生。替米沙坦治疗还能有效减轻尿路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路功能障碍的发病机制有关。本研究提出了膀胱中药理相关受体的激动剂或拮抗剂是治疗尿路功能障碍的有效治疗药物的可能性。较少

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