The roles of muscarinic receptor subtypes in the bladder contractions and the pathogenesis of overactive bladder

本研究探讨了M_2和M_3亚型受体在胆碱能神经-膀胱平滑肌传递中的功能作用，旨在为开发治疗膀胱过度活动症的有效药物提供策略。上述结果提示，不仅M_3亚型，而且M_2亚型也可直接引起膀胱收缩，而电压门控性Ca^<2 +>通道开放引起的膜去极化和随后的Ca^<2 +>内流是启动M_2和M_3亚型介导的收缩的关键。M_2受体在膀胱过度活动症中表达增加，M_2受体亚型可能是治疗膀胱过度活动症的潜在靶点。我们还确定了膀胱平滑肌中的非选择性阳离子通道，这是负责膜去极化，其性质有些不同，从那些有据可查的肠平滑肌阳离子通道。此外，我们发现，在膀胱条制剂中的毒蕈碱受体刺激产生的膜去极化和动作电位放电频率增加是相对非常差的比在单细胞制剂中观察到的，这表明膀胱组织被保护的机制，从过度兴奋后，毒蕈碱受体刺激可能存在。因此，这种保护机制的紊乱可能导致膀胱过度活动症的产生。

We have studied the functional roles of M_2 and M_3 subtypes of muscarinic receptors in the cholinergic nerve-bladder smooth muscle transmission, aiming to propose the strategy for development of effective drugs treating for the overactive bladder. The present results suggest that not only M_3 subtype, but also M_2 subtype directly produces bladder contractions and that membrane depolarization and subsequent Ca^<2+> influx due to the opening of voltage-gated Ca^<2+> channels are crucial for initiating both the M_2- and M_3-mediated contractions. Considering the fact that the density of M_2 receptors are increased in overactive bladder, M_2 subtype of muscarinic receptor may be a potential target for the treatment of overactive bladder. We also identified nonselective cation channels in bladder smooth muscles, which is responsible for the membrane depolarization and whose properties are somewhat different from those for well documented cation channels in intestinal smooth muscles. Furthermore, we revealed that the membrane depolarization and increased frequency of action potential discharges produced by muscarinic receptor stimulation in bladder strip preparations are relatively very poor than that observed in single cell preparation, suggesting that a mechanism by which the bladder tissue is protected from over-excitation upon muscarinic receptor stimulation may exist. Therefore, it is possible that disturbance of such protective mechanisms may lead to the generation of overactive bladder.