Characterization of neurotransmitter receptors in overactive bladder and drug discovery

本研究的目的是探讨膀胱过度活动症患者神经递质受体的变化，并为临床治疗提供依据。结果表明：（1）脊髓损伤大鼠膀胱有自发性收缩活动，膀胱肥大;（2）脊髓损伤大鼠膀胱[~ 3 H]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这些大鼠的不自主收缩活动的强度和频率密切相关。3）良性前列腺肥大（BPH）模型大鼠膀胱中存在肥大和M受体密度增加。这些数据表明，由于脊髓损伤和BPH，膀胱过度活动症中存在M受体活性增加，抗胆碱能药物是治疗膀胱过度活动症的有效药物。 ...更多信息 4）在大鼠膀胱匀浆中检测到大量的特异性[3 H]αβ-MeATP结合。αβ-MeATP、βγ-MeATP、MRS 2273、PPADS和苏拉明均能浓度依赖性地抑制膀胱[3 H]-ATP结合。结合亲和力按以下顺序更大：αβ-MeATP>βγ-MeATP>苏拉明>PPADS> MRS 2273。（P2 X亚型）存在于大鼠膀胱中，并且该受体是药物治疗的靶分子。（相对新颖的抗胆碱能剂）已显示通过口服给药与小鼠膀胱毒蕈碱受体显著结合，并且结合模式比奥昔布宁（一种常用的治疗膀胱过度活动症的抗胆碱能药物）更慢和更持久。口服托特罗定对毛果芸香碱引起的流涎的抑制作用明显弱于奥昔布宁，这些数据表明托特罗定在降低膀胱过度活动症患者口干发生率方面可能比奥昔布宁更有优势。少

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