Ligands for histamine H3 receptors modulate cell proliferation and migration in rat oxyntic mucosa
Ligands for histamine H3 receptors modulate cell proliferation and migration in rat oxyntic mucosa
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组胺 H3 受体配体调节大鼠泌酸粘膜细胞增殖和迁移
DOI：
10.1038/sj.bjp.0704853
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发表时间：
2002
影响因子：
7.3
通讯作者：
W. Schunack
中科院分区：
文献类型：
--
作者：
G. Morini;D. Grandi;W. Schunack
(R)- α-甲基组胺是组胺H3受体的选择性激动剂，可促进粘液分泌并增加粘液分泌细胞的数量和体积。研究了粘液细胞数量增加可能存在于胃上皮内稳态改变中的假设。(R)在处死前1 h（10-100 mg kg−1，通过胃内和腹膜内途径）和24 h（100 mg kg − 1，通过胃内途径）对大鼠给予α-甲基组胺。在处死前1 h，通过胃内途径给予α-甲基组胺的（S）-异构体（55.4 mg kg−1）（其对H3受体的效力比（R）-异构体低100倍）和H3受体激动剂FUB 407（9.14-91.35 mg kg−1）。在（R）-α-甲基组胺给药前30分钟，灌胃给予H1受体拮抗剂美托咪胺（30 mg kg − 1）、H2受体拮抗剂法莫替丁（3 mg kg − 1）、H3受体拮抗剂环丙昔芬（3 mg kg−1）和氯苄丙酸（30 mg kg−1）。对胃组织进行组织学和免疫组织化学处理。在1小时内，（R）-α-甲基组胺和FUB 407剂量依赖性地增加BrdU阳性细胞和凋亡细胞的数量。(S)- α-甲基组胺不能改变增殖和凋亡。（R）-α-甲基组胺引起的增殖增加可被环丙昔芬和氯苄丙酸逆转，但不能被美托洛尔和法莫替丁逆转。(R)- α-甲基组胺在给药后24 h加速向小凹细胞的分化及其向外迁移。这些作用被ciproxifan抵消。24 h凋亡率无明显变化。这些发现揭示了组胺H3受体配体在调节大鼠胃底粘膜细胞增殖和迁移中的主要作用。
(R)‐α‐methylhistamine, a selective agonist of histamine H3 receptors, promotes mucus secretion and increases the number and volume of mucus‐secreting cells. The hypothesis that the increased number of mucous cells could reside in an alteration of homeostasis in the gastric epithelium was investigated. (R)‐α‐methylhistamine was administered to rats 1 h (10–100 mg kg−1 by intragastric and by intraperitoneal route) and 24 h (100 mg kg−1 by intragastric route) prior to killing. The (S)‐isomer of α‐methylhistamine (55.4 mg kg−1), 100 times less potent than the (R)‐isomer at H3 receptors, and the H3‐receptor agonist FUB 407 (9.14–91.35 mg kg−1) were intragrastically administered 1 h prior to killing. The H1‐receptor antagonist mepyramine (30 mg kg−1), the H2‐receptor antagonist famotidine (3 mg kg−1), and the H3‐receptor antagonists ciproxifan (3 mg kg−1) and clobenpropit (30 mg kg−1) were intragastrically administered 30 min before (R)‐α‐methylhistamine. Gastric tissue was processed for histology and immunohistochemistry. Within 1 h, (R)‐α‐methylhistamine and FUB 407 dose‐dependently increased the number of BrdU‐positive cells and of apoptotic cells. (S)‐α‐methylhistamine failed to modify proliferation and apoptosis. The increase in proliferation by (R)‐α‐methylhistamine was reversed by ciproxifan and clobenpropit, but not by mepyramine and famotidine. (R)‐α‐methylhistamine accelerated the differentiation towards pit cells and their outward migration 24 h after its administration. These effects were counteracted by ciproxifan. The apoptosis rate was unaffected at 24 h. These findings reveal a primary role of histamine H3‐receptor ligands in modulating cell proliferation and migration in rat fundic mucosa.
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