FURTHER CHARACTERIZATION OF 5-HYDROXYTRYPTAMINE RECEPTORS (PUTATIVE 5-HT2B) IN RAT STOMACH FUNDUS LONGITUDINAL MUSCLE
FURTHER CHARACTERIZATION OF 5-HYDROXYTRYPTAMINE RECEPTORS (PUTATIVE 5-HT2B) IN RAT STOMACH FUNDUS LONGITUDINAL MUSCLE
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DOI：
10.1111/j.1476-5381.1994.tb13072.x
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发表时间：
1994-05-01
影响因子：
7.3
通讯作者：
BLACKBURN, TP
中科院分区：
文献类型：
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作者：
BAXTER, GS;MURPHY, OE;BLACKBURN, TP
1 本研究旨在从介导大鼠胃底纵向肌收缩的可能混合受体群体中分离和表征药理学同质的 5-羟色胺 (5-HT) 受体群体。我们的目的是扩展据报道在该制剂中表达的 5-HT2B 受体的药理学特征。2 为了最大限度地减少自发活动和环形肌对收缩反应的影响，使用了粘膜裸露的纵向肌肉的窄段（1-1.5 x 20 毫米）。在这些条件下，用聚吉林（100 μM，15 分钟）阻断单胺氧化酶会导致 5-甲氧基色胺 (5-MeO-T) 和色胺的浓度效应曲线向左位移。帕吉林和许多摄取抑制剂均不影响对 5-HT 的反应。3 在帕吉林预处理的制剂中，许多色胺类似物的效力顺序如下：5-MeO-T 大于或等于 α-Me-5-HT 大于或等于 5-HT>5-甲酰氨基色胺 (5-CT)>色胺>2-Me-5HT。此外，已知可作为 5-HT2A 或 5-HT2C 受体激动剂的几种配体，包括 1-m-氯苯基哌嗪 (m-CPP)、Ru 24969、MK 212 和 SCH 23390 也是大鼠眼底的激动剂，而舒马普坦、伦扎必利和 8-羟基-2-(二正丙氨基)四氢萘 (8-OH-DPAT) 是大鼠眼底的激动剂。非常虚弱或不活跃。除 2-Me-5-HT 和 m-CPP 外，大多数激动剂产生的单相浓度效应曲线与单个位点的相互作用一致。高浓度的 2-Me-5-HT 引起松弛，但被酚妥拉明 (1 μM) 阻断，表明与 α-肾上腺素受体相互作用。 m-CPP 经常引起具有第二收缩期的双相浓度效应曲线，在浓度高于拮抗 5-HT 反应所需的浓度时，育亨宾不敏感。4 LY 53857、甲硫替平、美西麦角、利坦色林和 ICI 170809 是大鼠眼底中 5-HT 的有效但不可克服的拮抗剂。相反，一些配体表现为可克服的拮抗剂，其效力顺序如下：萝芙素>育亨宾=美舒麦角大于或等于>米安舍林=SB 204070大于或等于WY 26703大于或等于SB 200646>吡伦匹隆大于或等于伦扎必利。 DAU 6285、格拉司琼、螺哌酮、酮色林、酚妥拉明和 GR 127935 在浓度高达 1 μM 时不影响对 5-KT 的反应。激动剂和浓度独立的拮抗作用支持激动剂和拮抗剂的单位点相互作用。5 我们得出结论，尽管萝芙辛和育亨宾的对映体选择性和亲和力存在微小差异，但大鼠胃底的 5-HT 受体与 I:he 最近克隆的 5-HT2B 受体保持了密切的药理学同一性。 SB 200646 证明了对大鼠胃底 5-HT 受体的一定选择性，应该为证实这一观点提供有用的配体，并允许在体外和体内区分 5-HT2B 功能。
1 The present study was undertaken to isolate and characterize pharmacologically homogeneous populations of 5-hydroxytryptamine (5-HT) receptors from a possible mixed receptor population mediating contraction of the longitudinal muscle of rat stomach fundus. Our aim was to extend the pharmacological characterization of the 5-HT2B receptor which is reported to be expressed in this preparation.2 To minimize spontaneous activity and any influence of circular muscle on the contractile response, narrow (1-1.5 x 20 mm) segments of mucosa-denuded longitudinal muscle were used. Under these conditions, blockade of monoamine oxidase with pargyline (100 mu M for 15 min) caused a leftward displacement of concentration-effect curves for both 5-methoxytryptamine (5-MeO-T) and tryptamine. Neither pargyline nor a number of uptake inhibitors affected responses to 5-HT.3 In pargyline pretreated preparations, the order of potency of a number of tryptamine analogues was as follows: 5-MeO-T greater than or equal to alpha-Me-5-HT greater than or equal to 5-HT>5-carboxamidotryptamine (5-CT)>tryptamine>2-Me-5HT. In addition several ligands known to act as agonists at either 5-HT2A or 5-HT2C receptors including 1-m-chlorophenylpiperazine (m-CPP), Ru 24969, MK 212 and SCH 23390 were also agonists in rat fundus whilst sumatriptan, renzapride and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were very weak or inactive. With the exception of 2-Me-5-HT and m-CPP, most agonists produced monophasic concentration-effect curves consistent with an interaction at a single site. High concentrations of 2-Me-5-HT evoked relaxations which were blocked by phentolamine (1 mu M) suggesting an interaction with alpha-adrenoceptors. m-CPP often evoked biphasic concentration-effect curves with a second contractile phase which was insensitive to yohimbine at concentrations higher than required for antagonism of responses to 5-HT.4 LY 53857, methiothepin, methysergide, ritanserin and ICI 170809 were potent but non-surmountable antagonists of 5-HT in rat fundus. In contrast, several ligands behaved as surmountable antagonists with the following order of potency: rauwolscine>yohimbine=mesulergine greater than or equal to>mianserin=SB 204070 greater than or equal to WY 26703 greater than or equal to SB 200646>pirenpirone greater than or equal to renzapride. DAU 6285, granisetron, spiperone, ketanserin, phentolamine and GR 127935 did not affect responses to 5-KT at concentrations up to 1 mu M. The agonist and concentration independent profile of antagonism supported a single site interaction for both agonists and antagonists.5 We conclude that despite small differences concerning the enantiomeric selectivity and affinity of rauwolscine and yohimbine, the close pharmacological identity of 5-HT receptors in rat stomach fundus and I:he recently cloned 5-HT2B receptor is maintained. SB 200646, which demonstrates some selectivity for 5-HT receptors in rat stomach fundus, should provide a useful ligand for confirmation of this view and allow discrimination of 5-HT2B function both in vitro and in vivo.