Receptor signaling mechanisms underlying muscarinic agonist-evoked contraction in guinea-pig ileal longitudinal smooth muscle
Receptor signaling mechanisms underlying muscarinic agonist-evoked contraction in guinea-pig ileal longitudinal smooth muscle
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DOI：
10.1038/sj.bjp.0705267
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发表时间：
2003-05-01
影响因子：
7.3
通讯作者：
Komori, S
中科院分区：
文献类型：
--
作者：
Unno, T;Kwon, SC;Komori, S
1 在豚鼠回肠纵肌中，毒蕈碱部分激动剂、4-(N-[3-氯苯基]-甲酰氧基)-2-丁炔基-三甲基铵 (McN-A343) 和毛果芸香碱均能平行增加张力和胞质 Ca2+ 浓度 ([Ca2+]c)，其 EC50 高于完全激动剂卡巴胆碱。 [Ca2+]c 或张力的最大反应在三种激动剂之间没有太大差异。 Ca2+ 通道阻滞剂尼卡地平显着抑制所有三种激动剂的作用2 对任何激动剂的收缩反应均被 M-2 受体选择性拮抗剂（N,N'-双[6-[[(2-甲氧基苯基)甲基]氨基]己基]-1,8-辛二胺四盐酸盐和11-[[2-[(二乙基氨基)甲基]-1-哌啶基]乙酰基]-5,11-二氢-6H-吡啶并[2,3-b][1,4]苯二氮卓-6-酮)，M-2拮抗剂敏感性的表观顺序为McN-A343>毛果芸香碱>卡巴胆碱。 M-3 受体选择性拮抗剂，1,1-二甲基-4-二苯乙酰氧基哌啶碘化物和达非那新，均严重抑制 McN-A343 的最大反应，而达非那新对毛果芸香碱也有类似的作用。两种 M3 拮抗剂在卡巴胆碱反应中均表现出竞争性。3 McN-A343 未能从细胞内储存的 Ca2+ 中释放出来，并且与卡巴胆碱相比，毛果芸香碱的 Ca2+ 释放作用非常弱。所有三种激动剂均能够增加收缩蛋白的 Ca2+ 敏感性。4 McN-A343 很少产生膜去极化，但总是加速尖峰放电。毛果芸香碱效应更常伴随着膜去极化，正如使用卡巴胆碱时常见的那样。5 结果表明，毒蕈碱激动剂诱发的收缩主要是由于与尖峰放电增加和肌丝 Ca2+ 敏化相关的 Ca2+ 进入整合所致，并且 Ca2+ 储存释放可能通过增强电膜反应间接促进收缩。他们还可能支持这样的观点：M-2 和 M-3 受体的相互作用在介导收缩反应中起着至关重要的作用。
1 In guinea-pig ileal longitudinal muscle, muscarinic partial agonists, 4-(N-[3-chlorophenyl]-carbomoyloxy)-2-butynyl-trimethylammonium (McN-A343) and pilocarpine, each produced parallel increases in tension and cytosolic Ca2+ concentration ([Ca2+]c) with a higher EC50 than that of the full agonist carbachol. The maximum response of [Ca2+]c or tension was not much different among the three agonists. The Ca2+ channel blocker nicardipine markedly inhibited the effects of all three agonists2 The contractile response to any agonist was antagonized in a competitive manner by M-2 receptor selective antagonists (N,N'-bis[6-[[(2-methoyphenyl)methyl]amino]hexyl]-1,8-octanediamine tetrahydrochloride and 11-[[2-[(diethlamino)methyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H-pyrido[2,3-b][ 1,4] benzodiazepine-6-one), and the apparent order of M-2 antagonist sensitivity was McN-A343>pilocarpine>carbachol. M-3 receptor selective antagonists, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide and darifenacin, both severely depressed the maximum response for McN-A343, while darifenacin had a similar action in the case of pilocarpine. Both M3 antagonists behaved in a competitive manner in the case of the carbachol response.3 McN-A343 failed to release Ca2+ from the intracellular stores, and the Ca2+-releasing action of pilocarpine was very weak compared with that of carbachol. All three agonists were capable of increasing Ca2+ sensitivity of the contractile proteins.4 McN-A343 rarely produced membrane depolarization, but always accelerated electrical spike discharge. Pilocarpine effect was more often accompanied by membrane depolarization, as was usually seen using carbachol.5 The results suggest that muscarinic agonist-evoked contractions result primarily from the integration of Ca2+ entry associated with the increased spike discharge and myofilaments Ca2+ sensitization, and that Ca2+ store release may contribute to the contraction indirectly via potentiation of the electrical membrane responses. They may also support the idea that an interaction of M-2 and M-3 receptors plays a crucial role in mediating the contraction response.