对介导豚鼠回肠黏膜“持续”短路电流反应的5-羟色胺受体的研究。
Investigation of the 5-hydroxytryptamine receptor mediating the 'maintained' short-circuit current response in guinea-pig ileal mucosa.
作者信息
Scott C M, Bunce K T, Spraggs C F
机构信息
Department of Gastrointestinal Pharmacology, Glaxo Group Research Ltd., Ware, Herts.
出版信息
Br J Pharmacol. 1992 Aug;106(4):877-82. doi: 10.1111/j.1476-5381.1992.tb14428.x.
Abstract
- 5-Hydroxytryptamine (5-HT) stimulated a biphasic increase in short-circuit current (SCC) in guinea-pig isolated ileal mucosa. The initial 'spike' response to 5-HT was inhibited by tetrodotoxin (0.3 microM). We have investigated the 5-HT receptor mechanism(s) controlling the second 'maintained' component of the response which remained after treatment with tetrodotoxin. 2. 5-HT stimulated concentration-related increases in SCC with an EC50 value of 5.4 microM. Isobutyl-methylxanthine (IBMX, 10 microM) produced a six fold leftward shift of this concentration-response curve, suggesting the involvement of a cyclic nucleotide(s) in these responses. 3. In the presence of IBMX, 5-HT stimulated reproducible increases in SCC with an EC50 value of 0.9 microM. The rank order of potency of indole agonists in these tests was 5-HT greater than or equal to 5-methoxytryptamine greater than 5-carboxamidotryptamine = alpha-methyl-5-HT much greater than 2-methyl-5-HT. 4. The substituted benzamides were partial agonists. Metoclopramide and cisapride produced approximately 20% of the 5-HT maximum, and renzapride and R,S-zacopride produced approximately 50% of the 5-HT maximum. Metoclopramide and cisapride inhibited the SCC responses to 5-HT with apparent pKB values of 4.8 and 7.0 respectively. 5. The SCC responses to 5-HT were not inhibited by antagonists selective for 5-HT1 (methysergide, methiothepin), 5-HT2 (ketanserin) or 5-HT3 (ondansetron, ICS205-930) receptors. 6. The SCC responses to 5-methoxytryptamine, 5-carboxamidotryptamine, alpha-methyl-5-HT and R,S-zacopride, but not 5-HT, were selectively inhibited by high concentrations of ICS205-930 with apparent pKB values of approximately 6.7. A possible interpretation of these results is that the 'maintained' SCC response to 5-HT is mediated by a heterogeneous population of 5-HT receptors. One of these receptors exhibits the characteristics of the putative 5-HT4 receptor.
摘要
5-羟色胺（5-HT）刺激豚鼠离体回肠黏膜的短路电流（SCC）出现双相增加。对5-HT的初始“尖峰”反应被河豚毒素（0.3微摩尔）抑制。我们研究了控制在用河豚毒素处理后仍存在的反应的第二个“持续”成分的5-HT受体机制。
5-HT刺激SCC浓度依赖性增加，EC50值为5.4微摩尔。异丁基甲基黄嘌呤（IBMX，10微摩尔）使该浓度-反应曲线向左移动6倍，表明环核苷酸参与了这些反应。
在存在IBMX的情况下，5-HT刺激SCC出现可重复增加，EC50值为0.9微摩尔。在这些试验中吲哚激动剂的效力顺序为5-HT≥5-甲氧基色胺＞5-羧酰胺基色胺=α-甲基-5-HT＞＞2-甲基-5-HT。
取代苯甲酰胺是部分激动剂。甲氧氯普胺和西沙必利产生约为5-HT最大反应的20%，雷尼必利和R,S-扎考必利产生约为5-HT最大反应的50%。甲氧氯普胺和西沙必利分别以表观pKB值4.8和7.0抑制对5-HT的SCC反应。
对5-HT的SCC反应不受对5-HT1（麦角新碱、甲硫噻平）、5-HT2（酮色林）或5-HT3（昂丹司琼、ICS205-930）受体有选择性的拮抗剂抑制。
对5-甲氧基色胺、5-羧酰胺基色胺、α-甲基-5-HT和R,S-扎考必利的SCC反应，但不是对5-HT的反应，被高浓度的ICS205-930选择性抑制，表观pKB值约为
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