Chan Sze Wa, He Jufang, Lin Ge, Rudd John A, Yamamoto Kouichi
Emesis Research Group, Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
Eur J Pharmacol. 2007 Jul 2;566(1-3):185-91. doi: 10.1016/j.ejphar.2007.03.050. Epub 2007 Apr 6.
Glucagon-like peptide-1 (GLP-1) receptor agonists have been reported to modulate gastrointestinal motility but the mechanism is essentially unknown. In the present studies, we investigated the potency and mechanism of action of GLP-1 receptor ligands on the isolated ileum of Suncus murinus, an insectivore used in anti-emetic research. Ileal segments were mounted in organ baths containing Kreb's solution. Cumulative concentration-response curves to GLP-1 (7-36) amide (0.1-300 nM) and exendin-4 (0.1-100 nM) were constructed in the absence and presence of exendin (9-39) amide (0.3-3 nM). GLP-1 (7-36) amide and exendin-4 induced concentration-dependent contractions yielding pEC50 values of 8.4+/-0.2 and 8.4+/-0.4, respectively. Exendin (9-39) antagonized the action of both agonists in a non-competitive reversible manner, with apparent pKB values of 9.5 and 9.7, respectively. Tetrodotoxin (1 microM), atropine (1 microM) and hexamethonium (500 microM) were used to determine the contractile mechanism of action of exendin-4. Tetrodotoxin and atropine significantly antagonized (P<0.01) the contractile action of exendin-4 (10 nM); hexamethonium (500 microM) had no action. These studies suggest that GLP-1 receptor agonists contract the ileum indirectly via postganglionic enteric neurones and an involvement of muscarinic receptors. These studies provide information relevant to the use of this species to estimate the therapeutic indexes of GLP-1 receptor agonists.
据报道，胰高血糖素样肽-1（GLP-1）受体激动剂可调节胃肠动力，但其机制尚不清楚。在本研究中，我们研究了GLP-1受体配体对食虫目动物臭鼩分离回肠的作用强度及作用机制，臭鼩常用于抗呕吐研究。将回肠段安装在含有克雷布斯溶液的器官浴槽中。在不存在和存在艾塞那肽（9-39）酰胺（0.3-3 nM）的情况下，构建对GLP-1（7-36）酰胺（0.1-300 nM）和艾塞那肽-4（0.1-100 nM）的累积浓度-反应曲线。GLP-1（7-36）酰胺和艾塞那肽-4诱导浓度依赖性收缩，其pEC50值分别为8.4±0.2和8.4±0.4。艾塞那肽（9-39）以非竞争性可逆方式拮抗两种激动剂的作用，其表观pKB值分别为9.5和9.7。使用河豚毒素（1 μM）、阿托品（1 μM）和六甲铵（500 μM）来确定艾塞那肽-4的收缩作用机制。河豚毒素和阿托品显著拮抗（P<0.01）艾塞那肽-4（10 nM）的收缩作用；六甲铵（500 μM）无作用。这些研究表明，GLP-1受体激动剂通过节后肠神经元间接使回肠收缩，且涉及毒蕈碱受体。这些研究为利用该物种评估GLP-1受体激动剂的治疗指数提供了相关信息。
