Activation of muscarinic receptors in rat bladder sensory pathways alters reflex bladder activity
Activation of muscarinic receptors in rat bladder sensory pathways alters reflex bladder activity
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DOI：
10.1523/jneurosci.4694-07.2008
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发表时间：
2008-02-20
影响因子：
5.3
通讯作者：
De Groat, William C.
中科院分区：
文献类型：
--
作者：
Kullmann, F. Aura;Artim, Debra E.;De Groat, William C.
抗毒蕈碱药物影响膀胱感觉症状，如尿急和尿频，可能是通过作用于位于膀胱感觉通路（包括初级传入神经和尿道刺激）中的毒蕈碱乙酰胆碱受体（mAChR）。然而，这些受体的表达和功能还不清楚。本研究探讨了mAChR在乌拉坦麻醉大鼠体内膀胱感觉通路中的作用。膀胱内给药的mAChR激动剂oxotremorine methiodide（OxoM）引起浓度依赖性的兴奋和抑制作用的排尿频率。这些影响被阻断膀胱内注射的mAChR拮抗剂阿托品硝酸甲酯（5 μ M）和辣椒素脱敏C-纤维传入神经的大鼠预处理缺席。低浓度的OxoM（5 μ M）降低排尿频率约30%，通过L-NAME（N-ω-硝基-L-精氨酸甲酯盐酸盐; 5 mg/kg; i. v.）抑制一氧化氮（NO）合成，该作用减弱。高浓度的OxoM（40 μ M）使排尿频率增加了45%，这一作用通过用PPADS（0.1- 1 mM;膀胱内）阻断嘌呤能受体而减弱。mAChR激动剂刺激培养的尿路上皮细胞释放ATP。静脉内给予OxoM（0.01-5 μ g/kg）不能模拟膀胱内对排尿频率的影响。这些结果表明，位于膀胱腔表面附近的mAChR的激活通过涉及ATP和NO释放的机制影响排尿功能，推测是从尿道，这反过来又可以作用于膀胱C纤维传入神经，以改变其放电特性。这些结果表明，尿路上皮传入神经的相互作用可以影响反射排尿功能。
Antimuscarinic drugs affect bladder sensory symptoms such as urgency and frequency, presumably by acting on muscarinic acetylcholine receptors (mAChRs) located in bladder sensory pathways including primary afferent nerves and urothelium. However, the expression and the function of these receptors are not well understood. This study investigated the role of mAChRs in bladder sensory pathways in vivo in urethane anesthetized rats. Intravesical administration of the mAChR agonist oxotremorine methiodide (OxoM) elicited concentration-dependent excitatory and inhibitory effects on the frequency of voiding. These effects were blocked by intravesical administration of the mAChR antagonist atropine methyl nitrate (5 mu M) and were absent in rats pretreated with capsaicin to desensitize C-fiber afferent nerves. Low concentrations of OxoM (5 mu M) decreased voiding frequency by similar to 30%, an effect blunted by inhibiting nitric oxide (NO) synthesis with L-NAME (N-omega-nitro-L-arginine methyl ester hydrochloride; 5 mg/kg; i.v.). High concentrations of OxoM (40 mu M) increased voiding frequency by similar to 45%, an effect blunted by blocking purinergic receptors with PPADS(0.1-1mM; intravesically). mAChR agonists stimulated release of ATP from cultured urothelial cells. Intravenous administration of OxoM (0.01-5 mu g/kg) did not mimic the intravesical effects on voiding frequency. These results suggest that activation of mAChRs located near the luminal surface of the bladder affects voiding functions via mechanisms involving ATP and NO release presumably from the urothelium, that in turn could act on bladder C-fiber afferent nerves to alter their firing properties. These findings suggest that the urothelial-afferent nerve interactions can influence reflex voiding function.