通过组胺3受体亚型对肠嗜铬样细胞组胺分泌的自身调节。

Autoregulation of enterochromaffin-like cell histamine secretion via the histamine 3 receptor subtype.

作者信息

Kidd M, Tang L H, Miu K, Lawton G P, Sandor A, Modlin I M

机构信息

Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA.

出版信息

Yale J Biol Med. 1996 Jan-Feb;69(1):9-19.

PMID:9041685

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2588967/

Abstract

INTRODUCTION

The neuroendocrine histamine-secreting cell of the gastric fundus, the enferochromaffin-like cell, is the principal regulator of parietal cell acid secretion. We have proposed that histamine may regulate its own synthesis and release via an autocrine mechanism. The purpose of this study was to evaluate the role of the histamine receptor subtypes H1, H2 and H3 in the regulation of this phenomenon.

METHODS

Purified ECL cells were isolated by pronase digestion and EDTA exposure of the rat stomach, followed by particle size and density separation using counterflow elutriation and Nycodenz gradient centrifugation, 24-hr cultured cells were pretreated for 30 min with the agents; H1 receptor agonist (2-[(3-trimethyl)-diphenyl] histamine) (TMPH), H1 receptor antagonist (terfenadine); H2 receptor agonist (dimaprit) or antagonist (cimetidine or loxitidine); or H3 receptor agonist (imetit) or antagonist (thioperamide) (all tested, 10(-10)-10(-6) M). Gastrin was then used to stimulate histamine secretion. Histamine secretion was quantified by specific enzyme-immunoassay.

RESULTS

Basal histamine secretion was 2.7 +/- 0.14 nmol/10(3) cells. Gastrin-stimulated (10 nM) levels were 4.6 +/- 0.4 nmol/10(3) cells (p < .01). TMPH inhibited both basal and gastrin driven histamine secretion with a maximal effect (34 percent) (1.78 +/- 0.08 nmol/10(3) cells) and an IC50 of > 5 x 10(-7) M. H1 receptor antagonism did not alter histamine secretion alone or in combination with gastrin. Neither H2 receptor stimulation nor antagonism had any effect on histamine secretion alone or in combination with gastrin. Gastrin-induced histamine secretion was dose-dependently inhibited by imetit (H3 agonist) with a maximal effect (2.4 +/- 0.6 nmol/10(3) cells) (p < .05) and an IC50 of 10(-9) M. Conversely, Thioperamide (H3 antagonist) dose-dependently augmented gastrin-stimulated histamine secretion with a maximum effect (5.7 +/- 0.5 nmol/10(3) cells) (p < .05) at 10(-8) M and an EC50 of 7 x 10(-10) M.

CONCLUSION

These data are consistent with the presence of an H3 receptor on the ECL cell which modulates gastrin-stimulated histamine secretion. Our observations support the proposal that a histamine-mediated short-loop autocrine regulatory mechanism of ECL cell secretion exists.

摘要

引言

胃底的神经内分泌组胺分泌细胞，即肠嗜铬样细胞，是壁细胞胃酸分泌的主要调节者。我们曾提出组胺可能通过自分泌机制调节其自身的合成与释放。本研究的目的是评估组胺受体亚型H1、H2和H3在调节这一现象中的作用。

方法

通过用链霉蛋白酶消化和EDTA处理大鼠胃来分离纯化肠嗜铬样细胞，随后使用逆流淘析和Nycodenz梯度离心进行粒度和密度分离，将培养24小时的细胞用以下试剂预处理30分钟：H1受体激动剂（2-[(3-三甲基)-二苯基]组胺）（TMPH）、H1受体拮抗剂（特非那定）；H2受体激动剂（二甲双胍）或拮抗剂（西咪替丁或洛西替丁）；或H3受体激动剂（碘替丁）或拮抗剂（硫代酰胺）（均在10⁻¹⁰ - 10⁻⁶ M浓度下测试）。然后用胃泌素刺激组胺分泌。通过特异性酶免疫测定法定量组胺分泌。

结果

基础组胺分泌量为2.7±0.14 nmol/10³个细胞。胃泌素刺激（10 nM）后的水平为4.6±0.4 nmol/10³个细胞（p < 0.01）。TMPH抑制基础和胃泌素驱动的组胺分泌，最大效应为34%（1.78±0.08 nmol/10³个细胞），IC50>5×10⁻⁷ M。H1受体拮抗作用单独或与胃泌素联合使用时均未改变组胺分泌。H2受体刺激或拮抗作用单独或与胃泌素联合使用时对组胺分泌均无任何影响。胃泌素诱导的组胺分泌被碘替丁（H3激动剂）剂量依赖性抑制，最大效应为（2.4±0.6 nmol/10³个细胞）（p < 0.05），IC50为10⁻⁹ M。相反，硫代酰胺（H3拮抗剂）剂量依赖性增强胃泌素刺激的组胺分泌，在10⁻⁸ M时最大效应为（5.7±0.5 nmol/10³个细胞）（p < 0.05），EC50为7×10⁻¹⁰ M。