Differential roles of M2 and M3 muscarinic receptor subtypes in modulation of bladder afferent activity in rats.
Differential roles of M2 and M3 muscarinic receptor subtypes in modulation of bladder afferent activity in rats.
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DOI：
10.1016/j.urology.2009.12.013
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发表时间：
2010-04
期刊：
影响因子：
2.1
通讯作者：
Yoshimura N
中科院分区：
文献类型：
--
作者：
Matsumoto Y;Miyazato M;Furuta A;Torimoto K;Hirao Y;Chancellor MB;Yoshimura N
有人提出尿路上皮调节膀胱传入通路的活动。然而，毒蕈碱乙酰胆碱受体（mAChR）亚型在局部膀胱传入激活中的差异作用尚不清楚。我们研究了各种mAChR拮抗剂，包括选择性M2和M3 mAChR拮抗剂对膀胱过度活动的影响。用聚氨酯麻醉的雌性大鼠进行膀胱测量。我们检测了膀胱内给药抗毒菌药（非选择性mAChR拮抗剂；硫酸阿托品、酒石酸托特罗定和盐酸丙丙碱，m2选择性拮抗剂；马来酸二甲胺钠和半水合甲氧曲明，m3选择性拮抗剂；氢溴酸达利那新和4-DAMP）对氧tremorine- m （Oxo-M；非选择性mAChR激动剂）诱导的膀胱过度活动的影响。膀胱内给药Oxo-M （200 μM）引起膀胱过度活动，表现为收缩间隔时间缩短、膀胱容量和压力阈值降低。非选择性或m2选择性拮抗剂（30-60 μM）可阻断这些作用，而m3选择性拮抗剂（150 μM）不能抑制这种过度活性。当单独静脉滴注时，抗毒蕈碱药物（非选择性、m2选择性或m3选择性拮抗剂）均不影响任何膀胱参数。M2 mAChR亚型在膀胱传入活动的局部胆碱能调节中起重要作用，导致正常大鼠膀胱过度活动。因此，如果乙酰胆碱机制的增强参与了膀胱过度活动的发病机制，那么抗毒蕈碱类药物对M2 mAChR具有拮抗作用，可能更有利于膀胱过度活动患者的治疗。
It has been proposed that the urothelium modulates the activity of bladder afferent pathways. However, the differential roles of muscarinic acetylcholine receptor (mAChR) subtypes in local bladder afferent activation remain unclear. We investigated the effects of various mAChR antagonists including selective M2 and M3 mAChR antagonists on bladder overactivity. Cystometry was performed in urethane anesthetized female rats. We examined the effects of intravesical administration of antimuscarinic agents (non-selective mAChR antagonists; atropine sulfate, tolterodine tartrate and propiverine hydrochloride, M2-selective antagonists; dimethindene maleate and methoctramine hemihydrate, M3-selective antagonists; darifenacin hydrobromide and 4-DAMP) on bladder overactivity induced by oxotremorine-M (Oxo-M; non-selective mAChR agonist). Intravesical administration of Oxo-M (200 μM) elicited bladder overactivity as evidenced by decreased intercontraction interval, bladder capacity and pressure threshold. These effects were blocked by intravesical administration of non-selective or M2-selective antagonists (30–60 μM) whereas M3-selective antagonists (150 μM) did not suppress the overactivity. When instilled intravesically by itself, none of antimuscarinic agents (non-selective, M2-selective or M3-selective antagonists) affected any cystometric parameters. The M2 mAChR subtype plays an important role in the local cholinergic modulation of bladder afferent activity that contributes to bladder overactivity in normal rats. Therefore, it is expected that antimuscarinic agents that have antagonistic activity against M2 mAChR can be more beneficial for the treatment of patients with overactive bladder if enhanced ACh mechanisms are involved in pathogenesis of overactive bladder.
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影响因子：
2.1
作者：
Nishiguchi, J;Hayashi, Y;Yoshimura, N
通讯作者：
Yoshimura, N
影响因子：
3.6
作者：
Yoshimura, Naoki;Kaiho, Yasuhiro;Tyagi, Pradeep
通讯作者：
Tyagi, Pradeep
影响因子：
6.1
作者：
Bschleipfer, Thomas;Schukowski, Konstantin;Lips, Katrin S.
通讯作者：
Lips, Katrin S.
影响因子：
4
作者：
Fritz, N;Macrez, N;Morel, JL
通讯作者：
Morel, JL
影响因子：
5.3
作者：
Kullmann, F. Aura;Artim, Debra E.;De Groat, William C.
通讯作者：
De Groat, William C.