NMDAR in bladder smooth muscle is not a pharmacotherapy target for overactive bladder in mice.
NMDAR in bladder smooth muscle is not a pharmacotherapy target for overactive bladder in mice.
复制标题
膀胱平滑肌中的 NMDAR 不是小鼠膀胱过度活动症的药物治疗靶点
作者：
Xie X;Luo C;Liang JY;Huang R;Yang JL;Li L;Li Y;Xing H;Chen H
膀胱过度活动症（OAB）是一种常见的疾病，影响了大量的患者群体。N-甲基-D-天冬氨酸受体（NMDAR）在发展膀胱过度活动中具有作用，其药理学抑制抑制膀胱过度活动。OAB的常见发病机制涉及膀胱平滑肌（BSM）过度活动。在本研究中，产生了平滑肌特异性NMDAR敲除（SMNRKO）小鼠模型。来自SMNRKO小鼠的膀胱显示正常大小和重量，具有完整的膀胱壁和排列良好的BSM束。此外，SMNRKO小鼠具有正常的排尿模式和尿动力学以及BSM收缩性，表明BSM中的NMDAR对于正常生理膀胱形态和功能不是必需的。出乎意料的是，环磷酰胺（CTX）处理的SMNRKO和野生型（WT）小鼠在膀胱中具有相似的病理变化。此外，SMNRKO小鼠表现出类似的改变排尿模式和尿动力学异常和受损的BSM收缩性与WT小鼠相比，在顺铂治疗后。MK 801部分逆转了BSM诱导的病理性膀胱形态学改变，改善了膀胱功能障碍，但在WT小鼠和SMNRKO小鼠之间没有引起明显差异，提示BSM中NMDAR不参与病理性膀胱形态学改变和功能障碍。此外，将NMDAR激动剂或拮抗剂直接滴入CYP诱导的OAB中不影响膀胱尿动力学功能，表明BSM中的NMDAR不是MK 801治疗CYP诱导的膀胱炎的药物治疗靶点。结果表明，BSM中的NMDAR对于正常生理或病理膀胱形态和功能不是必需的，并且MK 801改善病理膀胱功能不是通过对BSM中的NMDAR的作用介导的。
Overactive bladder (OAB) is a common condition that affects a significant patient population. The N-methyl-D-aspartate receptor (NMDAR) has a role in developing bladder overactivity, pharmacological inhibition of which inhibits bladder overactivity. The common pathogenesis of OAB involves bladder smooth muscle (BSM) overactivity. In this study, a smooth muscle–specific NMDAR knockout (SMNRKO) mouse model was generated. The bladders from SMNRKO mice displayed normal size and weight with an intact bladder wall and well-arranged BSM bundles. Besides, SMNRKO mice had normal voiding patterns and urodynamics and BSM contractility, indicating that NMDAR in BSM was not essential for normal physiological bladder morphology and function. Unexpectedly, cyclophosphamide (CYP)-treated SMNRKO and wild-type (WT) mice had similar pathological changes in the bladder. Furthermore, SMNRKO mice displayed similar altered voiding patterns and urodynamic abnormalities and impaired BSM contractility compared with WT mice after CYP treatment. MK801 partially reversed the pathological bladder morphology and improved bladder dysfunction induced by CYP, but did not cause apparent differences between WT mice and SMNRKO mice, suggesting that NMDAR in BSM was not involved in pathological bladder morphology and function. Moreover, the direct instillation of NMDAR agonists or antagonists into the CYP-induced OAB did not affect bladder urodynamic function, indicating that NMDAR in BSM was not the pharmacotherapy target of MK801 for CYP-induced cystitis. The findings indicated that NMDAR in BSM was not essential for normal physiological or pathological bladder morphology and function, and MK801 improving pathological bladder function was not mediated by an action on NMDAR in BSM.
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DOI：
10.1111/luts.12193
发表时间：
2019-01
期刊：
Lower urinary tract symptoms
影响因子：
--
作者：
Chuang YC;Liu SP;Lee KS;Liao L;Wang J;Yoo TK;Chu R;Sumarsono B
通讯作者：
Sumarsono B
影响因子：
2.7
作者：
Ishida, F;Sato, T;Kawatani, M
通讯作者：
Kawatani, M
DOI：
10.1152/ajprenal.00318.2017
发表时间：
2017-12-01
影响因子：
4.2
作者：
Chen, Huan;Zhang, Lanlan;Yu, Weiqun
通讯作者：
Yu, Weiqun
DOI：
10.1152/ajplung.00402.2014
发表时间：
2015-06-15
影响因子：
4.9
作者：
Anaparti, Vidyanand;Ilarraza, Ramses;Moqbel, Redwan
通讯作者：
Moqbel, Redwan
影响因子：
7.5
作者：
Doronzo, Gabriella;Russo, Isabella;Anfossi, Giovanni
通讯作者：
Anfossi, Giovanni