Functional roles of muscarinic M2 and M3 receptors in mouse stomach motility: studies with muscarinic receptor knockout mice.
Functional roles of muscarinic M2 and M3 receptors in mouse stomach motility: studies with muscarinic receptor knockout mice.
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DOI：
10.1016/j.ejphar.2006.10.013
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发表时间：
2007-01
影响因子：
5
通讯作者：
T. Kitazawa;K. Hashiba;Jinshan Cao;T. Unno;S. Komori;M. Yamada;J. Wess;T. Taneike
中科院分区：
文献类型：
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作者：
T. Kitazawa;K. Hashiba;Jinshan Cao;T. Unno;S. Komori;M. Yamada;J. Wess;T. Taneike
用缺乏M_2受体和/或M_3受体的小鼠及其相应的野生型(WT)小鼠，研究了M受体在小鼠胃运动调节中的功能作用。M2R-KO和M3R-KO小鼠胃窦和胃底条单独应用卡巴胆碱(1：NM-30和μM)可产生浓度依赖性收缩，而M2和M3R-KO小鼠则无此效应。与WT小鼠比较，M受体缺陷小鼠的EC50(PEC50)的负对数(M2R-KO)或最大收缩幅度(M3R-KO)显著降低。在M3R-KO小鼠的胃条中，卡巴胆碱引起的收缩的紧张期减少。对4-二苯基乙酰氧基-N-甲基哌啶(4-DAMP)和11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5，11-dihydro-6H-pyrido[2，3-b][1，4]benzodiazepine-6-one(AF-DX116)的拮抗亲和力表明，M2R-KO和M3R-KO小鼠的收缩反应分别由M_3和M_2受体介导。电场刺激可引起毒扁豆碱和N-硝基-L-精氨酸甲酯(N-ω-硝基-L-精氨酸甲酯，N-NAME)处理的M2R-KO和M3R-KO小鼠胃底和胃窦条的频率依赖性收缩，但胆碱能收缩成分较WT小鼠显著减少。在M2/M3R-KO小鼠的胃条上，没有观察到EFS引起的胆碱能收缩，但阿托品抵抗的收缩比WT小鼠的胃条更明显。WT小鼠和M2/M3R-KO小鼠的胃排空功能相似，表明KO小鼠的胃运动功能与WT小鼠没有差异。结果表明，M_2和M_3受体均介导卡巴胆碱或EFS引起的小鼠胃收缩，但各受体对浓度-反应关系的贡献是不同的。虽然KO小鼠胃内胆碱能神经介导的反应受损，但KO小鼠胃排空功能与WT小鼠相同，可能是由于非胆碱能收缩途径代偿性增强所致。
Functional roles of muscarinic acetylcholine receptors in the regulation of mouse stomach motility were examined using mice genetically lacking muscarinic M2receptor and/or M3receptor and their corresponding wild-type (WT) mice. Single application of carbachol (1 nM–30 μM) produced concentration-dependent contraction in antral and fundus strips from muscarinic M2receptor knockout (M2R-KO) and M3receptor knockout (M3R-KO) mice but not in those from M2and M3receptors double knockout (M2/M3R-KO) mice. A comparison of the concentration–response curves with those for WT mice showed a significant decrease in the negative logarithm of EC50(pEC50) value (M2R-KO) or amplitude of maximum contraction (M3R-KO) in the muscarinic receptor-deficient mice. The tonic phase of carbachol-induced contraction was decreased in gastric strips from M3R-KO mice. Antagonistic affinity for 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX116) indicated that the contractile responses in M2R-KO and M3R-KO mice were mediated by muscarinic M3and M2receptors, respectively. Electrical field stimulation (EFS, 0.5–32 Hz) elicited frequency-dependent contraction in physostigmine- and Nω-nitro-l-arginine methylester (l-NAME)-treated fundic and antral strips from M2R-KO and M3R-KO mice, but the cholinergic contractile components decreased significantly compared with those in WT mice. In gastric strips from M2/M3R-KO mice, cholinergic contractions elicited by EFS were not observed but atropine-resistant contractions were more conspicuous than those in gastric strips from WT mice. Gastric emptying in WT mice and that in M2/M3R-KO mice were comparable, suggesting that motor function of the stomach in the KO mice did not differ from that in the WT mice. The results indicate that both muscarinic M2and M3receptors but not other subtypes mediate carbachol- or EFS-induced contraction in the mouse stomach but that the contribution of each receptor to concentration–response relationships is distinguishable. Although there was impairment of nerve-mediated cholinergic responses in the stomach of KO mice, gastric emptying in KO mice was the same as that in WT mice probably due to the compensatory enhancement of the non-cholinergic contraction pathway.