Characterization of neurotransmitter receptors in overactive bladder and drug discovery

本研究的目的是了解膀胱过度活动神经递质受体的改变，从而开发有效的药物治疗。结果表明：1)脊髓损伤大鼠膀胱出现不自主（自发）收缩活动，膀胱明显肥大。2)大鼠脊髓损伤导致膀胱[3H]NMS结合Bmax值显著升高，提示膀胱毒蕈碱受体密度上调。这种受体密度的增加与这些大鼠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）大鼠模型膀胱内毒蕈碱受体密度增大、肥大。这些数据表明，由于脊髓和bph2的损伤，过度活跃膀胱中毒蕈碱受体活性增加，抗胆碱能药物对减轻过度活跃膀胱的这些症状更有效。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和苏拉胺以浓度依赖的方式抑制膀胱特异性[3H]-ATP结合。结合亲和力依次为：αβ-MeATP>βγ-MeATP>suramine>PPADS>MRS2273。这些数据表明，ATP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（一种较新的抗胆碱能药物）经口服可与小鼠膀胱毒蕈碱受体显著结合，其结合方式比治疗膀胱过度活跃常用的抗胆碱能药物奥昔布宁更缓慢，持续时间更长。口服托特罗定对匹罗卡品引起的唾液分泌的抑制作用明显弱于奥昔布宁。这些数据表明，托特罗定在膀胱过度活动患者的口干发生率较低方面可能比奥昔布宁更有利。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