兔离体肠系膜动脉预收缩所揭示的血管收缩剂5HT1样受体的存在

Presence of vasoconstrictor 5HT1-like receptors revealed by precontraction of rabbit isolated mesenteric artery.

作者信息

Choppin A, O'Connor S E

机构信息

Synthélabo Recherche, Department of Preclinical Research, Bagneux, France.

出版信息

Br J Pharmacol. 1995 Jan;114(2):309-14. doi: 10.1111/j.1476-5381.1995.tb13228.x.

DOI:10.1111/j.1476-5381.1995.tb13228.x

PMID:7881730

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1510220/

Abstract

A series of 5-hydroxytryptamine (5-HT) receptor agonists including 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced little or no contraction of rabbit isolated mesenteric arteries under resting tone conditions, even at concentrations up to 10(-4) M. 2. When the same agonists were retested in mesenteric artery preparations pre-contracted with the thromboxane-mimetic, U46619, each demonstrated concentration-related vasoconstrictor activity. 5-CT and 5-HT were especially potent and effective in this model giving EC50 values of 4.3 x 10(-9) M and 1.6 x 10(-8) M respectively and maximum effects equivalent to those of KCl 80 mM. In preparations precontracted by U46619 (conditions retained throughout the rest of the study) the order of agonist potency was 5-CT > 5-HT > RU 24969 = sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) > cisapride. 3. The vasoconstrictor effects of 5-CT were competitively antagonized by methiothepin (pA2 8.20) but resistant to antagonism by a range of other 5-HT receptor antagonists, i.e. pindolol (5-HT1A/5-HT1B), propranolol (5-HT1B), spiperone (5-HT2A), ondansetron (5-HT3), ICS 205930 (5-HT3/5-HT4) and SDZ 205557 (5-HT4). 5-CT responses were slightly antagonized by a high concentration of ritanserin (5-HT2A/5-HT2C). Responses to 5-HT and sumatriptan were also antagonized by methiothepin with similar affinity (pA2/pKB values congruent to 8.0). 4. Metergoline and rauwolscine (10(-7)-10(-6) M) antagonized the effects of 5-CT in a non-competitive fashion giving pKBapp values of 7.13 (metergoline) and 6.86 (rauwolscine). 5. Vasoconstrictor responses to 5-HT were not modified in the presence of ritanserin (3 x 10-7 M) orspiperone (3 x 10-7 M) and only modestly antagonized by ketanserin (10-6 M) suggesting that 5-HT2Areceptors do not make a significant contribution in this model.6. Hence, precontraction of rabbit mesenteric arteries reveals potent vasoconstrictor effects of 5-HT and related agonists. Based on the agonist potency order and the antagonist studies performed, the receptor subtype responsible has the characteristics of a 5-HT1-like (probably 5-HTlD) receptor. This study therefore demonstrates a particularly striking example of vasoconstrictor synergy involving 5-HT1-like receptors.

摘要

一系列5-羟色胺（5-HT）受体激动剂，包括5-HT、5-羧基酰胺色胺（5-CT）和舒马曲坦，在静息张力条件下，即使浓度高达10⁻⁴ M，对兔离体肠系膜动脉也几乎不产生或不产生收缩作用。2. 当在预先用血栓素类似物U46619预收缩的肠系膜动脉制剂中重新测试相同的激动剂时，每种激动剂均表现出浓度相关的血管收缩活性。在该模型中，5-CT和5-HT特别有效，其半数有效浓度（EC50）值分别为4.3×10⁻⁹ M和1.6×10⁻⁸ M，最大效应与80 mM氯化钾相当。在由U46619预收缩的制剂中（在本研究的其余部分均保持该条件），激动剂效力顺序为5-CT＞5-HT＞RU 24969 = 舒马曲坦＞8-羟基-2-（二正丙基氨基）四氢萘（8-OHDPAT）＞西沙必利。3. 5-CT的血管收缩作用被甲硫噻嗪竞争性拮抗（pA2 8.20），但对一系列其他5-HT受体拮抗剂的拮抗作用具有抗性，即吲哚洛尔（5-HT1A/5-HT1B）、普萘洛尔（5-HT1B）、螺哌隆（5-HT2A）、昂丹司琼（5-HT3）、ICS 205930（5-HT3/5-HT4）和SDZ 205557（5-HT4）。高浓度的利坦色林（5-HT2A/5-HT2C）对5-CT反应有轻微拮抗作用。对5-HT和舒马曲坦的反应也被甲硫噻嗪以相似亲和力拮抗（pA2/pKB值相当于8.0）。4. 麦角新碱和育亨宾（10⁻⁷ - 10⁻⁶ M）以非竞争性方式拮抗5-CT的作用，其表观平衡解离常数（pKBapp）值分别为7.13（麦角新碱）和6.86（育亨宾）。5. 在存在利坦色林（3×10⁻⁷ M）或螺哌隆（3×10⁻⁷ M）的情况下，对5-HT的血管收缩反应未改变，仅被酮色林（10⁻⁶ M）适度拮抗，这表明5-HT2A受体在该模型中不起重要作用。6. 因此，兔肠系膜动脉的预收缩揭示了5-HT及相关激动剂的强效血管收缩作用。基于激动剂效力顺序和所进行的拮抗剂研究，所涉及的受体亚型具有5-HT1样（可能是5-HT1D）受体的特征。因此，本研究证明了涉及5-HT1样受体的血管收缩协同作用的一个特别显著的例子。