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Characterization of neurotransmitter receptors in overactive bladder and drug discovery

膀胱过度活动症神经递质受体的表征和药物发现

基本信息

批准号：
15591703
负责人：
YAMADA Shizuo
金额：
$ 2.3万
依托单位：
University of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591703/
关键词：
Overactive bladder Benign prostatic hypertrphy Neurotransmitter receptors Rat model with spinal cord injury Radioreceptor assay Receptor binding parameters Cystometry method ムスカリン性受容体 [3H]NMS 解離定数最大結合部位数

项目摘要

The aim of this study is to characterize alteration of neurotransmitter receptors in overactive bladder and then to develop effective drug therapy. The results obtained here are as follows:1) There were involuntary (spontaneous) contractile activity (in the cystometry) and significant hypertrophy in the bladder of rats received injury of spinal cord.2) The injury of spinal cord in rats brought about a significant increase in the Bmax value for bladder [3H]NMS binding, suggesting up regulation of muscarinic receptor density in the bladder. This increase in the receptor density correlated well with the intensity and frequency of involuntary contractile activity in these rats.3) There were hypertrophy and increase in the muscarinic receptor density in the bladder of rat model with benign prostatic hypertrophy (BPH). These data suggest that there is an increased muscarinic receptor activity in the overactive bladder due to the injury of spinal cord and BPHand that anticholinergic drugs are … More effective to attenuate these symptom in the overactive bladder.4) Significant amount of specific [3H]αβ-MeATP binding was detected in the homogenates of rat bladder. Specific [3H]-ATP binding in the bladder was inhibited by αβ-MeATP, βγ-MeATP, MRS2273, PPADS and suramine in the concentration dependent manner. The binding affinity was greater in, the following order: αβ-MeATP>βγ-MeATP>suramine>PPADS>MRS2273.These data suggest that ATP receptor (P2X subtype) is present in the rat bladder and that this receptor is a target molecule for the drug therapy.5) Tolterodine (relatively novel anticholinergic agent) has been shown to bind significantly to the mouse bladder muscarinic receptors by oral administration, and the mode of binding is more slow and longer-lasting than that of oxybutynin, a commonly used anticholinergic agent to treat overactive bladder. The inhibition of pilocarpine evoked salivation by oral administration of tolterodine was significantly weaker than that of oxybutynin.These data indicate that tolterodine may be more advantageous than oxybutynin in terms of low incidence of dry mouth in patients with overactive bladder. Less

本研究的目的是了解膀胱过度活动症患者神经递质受体的变化特征，从而探索有效的药物治疗方法。结果如下：(1)大鼠脊髓损伤后，膀胱有不自主(自发)收缩活动，膀胱明显肥大。(2)脊髓损伤后，大鼠膀胱[~3H]NMS结合的Bmax值显著增加，提示膀胱M受体密度上调。这种受体密度的增加与大鼠非自主收缩活动的强度和频率有很好的相关性。3)良性前列腺肥大(BPH)模型大鼠膀胱内M受体密度增加和肥大。这些数据表明，由于脊髓和BP损伤，过度活动的膀胱中M受体活性增加，抗胆碱能药物为…。4)在大鼠膀胱匀浆中检测到大量的特异性[~3H]αβ-MeATP结合。αβ-MeATP、βγ-MeATP、MRS2273、PPADS和苏拉明均以浓度依赖的方式抑制膀胱特异性[~3H]-ATP结合。结合亲和力更强的顺序如下：αβ-MeATP&gt；βγ-MeATP&gt；suramine&gt；PPADS&gt；MRS2273.These数据表明，三磷酸腺苷受体(P2X亚型)存在于大鼠膀胱中，该受体是药物治疗的靶分子。5)托特罗定(一种相对新型的抗胆碱能药物)已被证明通过口服给药可与小鼠膀胱的M受体显著结合，而且结合模式比奥昔布宁更慢，持续时间更长，奥昔布宁是一种常用的抗胆碱能药物，用于治疗膀胱过度活动。口服托特罗定对匹罗卡品诱发的唾液分泌的抑制作用明显弱于奥昔布宁，提示托特罗定在膀胱过度活动症患者口干发生率方面可能比奥昔布宁更具优势。较少