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

1)清醒大鼠膀胱内注入P2X3受体拮抗剂TNP-ATP后，膀胱容量和排尿阈值压力呈剂量依赖性增加。而P2X受体激动剂三磷酸腺苷可降低这两个参数，TNP-三磷酸腺苷可阻断三磷酸腺苷的作用。这些结果表明，P2X3受体的激活促进了大鼠膀胱的尿路上皮-传入神经传导系统。2)利用M2或M3基因敲除小鼠的清醒膀胱计量学研究了M2和M3受体在下尿路功能中的生理作用。结论：M_3受体是引起排尿膀胱收缩的主要M受体亚型，M_2受体的作用次之。3)对9例良性前列腺增生症(BPH)患者和5例I-…患者进行了三种不同频率的膀胱内电刺激阈值的研究间质性膀胱炎(IC)较多。我们发现IC组的三个频率的阈值均显著低于BPH组。4)对5例逼尿肌过度活动(DO)患者和6例对标准保守治疗无效的间质性膀胱炎(IC)患者进行了膀胱内注射瑞尼费曲霉毒素(RTX，1〓M)的临床和尿动力学研究。5例DO患者中有4例在滴注后1周内起效，起效时间3~9个月。IC组6例患者治疗后1周内储尿症状均有改善，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。5)本研究结果表明，尿路上皮-神经传导系统是治疗顽固性膀胱储存障碍，如DO和IC的一个有前途的治疗靶点。较少

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