Development of new drugs targeting at the urothelial-afferent neurotransduction system for bladder storage dysfunction

1)在意识清醒的大鼠中，膀胱内灌注P2X3受体拮抗剂TNP-ATP可剂量依赖性地增加膀胱容量和排尿阈压。另一方面，P2X受体的激动剂ATP降低了这两个参数，用TNP-ATP预处理可以阻断ATP的作用。这些结果提示P2X3受体的激活促进了大鼠膀胱尿路上皮-传入神经传导系统。2)利用M2或M3敲除小鼠，通过有意识的膀胱测量研究，探讨毒蕈碱M2和M3受体在下尿路功能中的生理作用。结论M3受体是主要的毒蕈碱受体亚型，负责排尿膀胱收缩，M2受体的作用次要（参考文献1）。3)研究了9例良性前列腺增生（BPH）患者和5例i…More间质性膀胱炎（IC）患者膀胱内尿路上皮电刺激的三种不同频率的阈值。我们发现，IC组三种频率的阈值均显著低于BPH组。膀胱内注射局麻药（0.5%布比卡因）增加了所有4例IC患者的阈值。4)对5例逼尿肌过度活跃（DO）患者和6例标准保守治疗无效的间质性膀胱炎（IC）患者膀胱内滴注树脂干扰素（RTX, 1〓M）的临床和尿动力学效果进行了观察。5例DO患者中有4例在注射后1周内出现缓解，疗效持续3-9个月。IC组6例患者在治疗后1周内尿潴留症状均有改善，膀胱疼痛评分和平均排尿量均有明显改善。然而，这些影响在2-3个月内消失。无不良事件报告。5)综上所述，本研究结果表明尿路上皮-传入神经转导系统是治疗顽固性膀胱贮积疾病（如DO和IC）的一个有希望的治疗靶点

1) In conscious rats, intravesical instillation of TNP-ATP, an antagonist for P2X3 receptors, dose-dependently increased bladder capacity and threshold pressure for voiding. On the other hand, ATP, an agonist for P2X receptors, decreased these two parameters, and pretreatment with TNP-ATP blocked the effect of ATP. Theses results suggest that activation of P2X3 receptors facilitates the urothelial-afferent neurotransduction system in the rat bladder.2) The physiological role of muscarinic M2 and M3 receptors in the lower urinary tract function was investigated in a conscious cystometric study by using M2 or M3 knockout mice. It is concluded that M3 receptor is the principal muscarinic receptor subtype responsible for voiding bladder contractions, and the role of M2 receptors is of minor importance (ref. 1).3) The threshold for intravesical urothelial electric stimulation with three different frequencies was investigated in 9 patients with benign prostatic hyperplasia (BPH) and 5 with i … More nterstitial cystitis (IC). We found that the threshold values, with all three frequencies, in IC group was significantly lower that those in BPH group. Intravesical instillation of a local anesthetic (0.5% bupivacain) increased the threshold in all 4 IC patients tested.4) The clinical and urodynamic effects of intravesical instillation of resiniferatoxin (RTX, 1〓M) were investigated in 5 patients with detrusor overactivity (DO) and 6 patients with interstitial cystitis (IC) resistant against standard conservative therapy. Four of 5 DO patients responded to the treatment within 1 week after the instillation, and the effect lasted for 3-9 months. In the IC group, all 6 patients showed improvement of their storage symptoms within 1 week after the treatment, and bladder pain score and mean voided volume were significantly improved. However, these effects disappeared within 2-3 months. No adverse events were reported.5) All together, the results of the present study indicate that urothelial-afferent neurotransduction system is a promising therapeutic targets in the treatment of intractable bladder storage disorders, such as DO and IC. Less