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CHARACTERIZATION OF GASTRIC ACID SECRATION BASED ON THE STUDY OF HISTAMINE H2 RECEPTOR AND HELICOBACTER PYROLI

基于组胺H2受体和幽门螺杆菌研究的胃酸分泌特征

基本信息

批准号：
10670512
负责人：
SAITO Toshihito
金额：
$ 1.98万
依托单位：
DEPARTMENT OF INTERNAL MEDICINE TOKYO WOMEN'S UNIVERSITY OF SCHOOL OF MEDICINE DAINI HOSPITAL
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

The histamine H2 receptor (H2R) is a target for major anti-ulcer drugs. H2 antagonists have been widely used for the treatment of peptic ulcer disorders since their discovery in the 1970s. The H2R was assumed to reside in gastric parietal cells and to be involved in gastric acid production via production of cyclic adenosine monophosphate (cAMP), although no direct evidence of pariental cells have been presented to date. In this study, we cloned the mouse H2R gene and generated a specific antibody, we immunohistochemically investigated gastric and subcellular localization of H2R. Next, we expressed human H2 receptor (HH2R) in Chinese hamster ovary cells (CHO) and directly investigated the effects of various H2 receptor antagonists. IT-066 inhibited ィイD13ィエD1H tiotidine binding and histamine stimulated cAMP production more potently than famotidine and ranitidine. In addition, preincubation of IT-066 marked inhibtory effects long after extensive washing. Paraformaldehyde fixation of cells blunted inhibition of ィイD13ィエD1H tiotidine binding induced by preincubation with IT-066, but not that by preincubation with famotidine or ranitidine. IT-066 has potent and long-lasting antagonisms on HH2R. At least one of the IT-066 binding sites is not shared by famotidine, ranitidine, or tiotidine and it affected by paraformaldehyde. Using HH2R expressed CHO, we also analyzed the effect of N-alfa-methylhistamine (NMeH) on cAMP production. NMeH is an H2 receptor agonist and produced by H.pyroli in gastric mucosa. NMeH was more potent in terms of cAMP production than histamine. Although NMeH inhibit acid secration via H3 receptor, it may stimultanously stimulate acid secration via H2 receptor.

组胺H2受体（H2 R）是主要抗溃疡药物的靶点。H2拮抗剂自20世纪70年代发现以来已广泛用于治疗消化性溃疡疾病。假设H2 R存在于胃壁细胞中，并通过环磷酸腺苷（cAMP）的产生参与胃酸的产生，尽管迄今为止还没有直接证据表明壁细胞存在。本研究克隆了小鼠H2 R基因，制备了特异性抗体，并对H2 R在小鼠胃和亚细胞中的定位进行了化学分析。接下来，我们在中国仓鼠卵巢细胞（CHO）中表达人H2受体（HH 2 R），并直接研究各种H2受体拮抗剂的作用。与法莫替丁和雷尼替丁相比，IT-066抑制组胺D13受体D1 H噻替丁结合和组胺刺激cAMP产生的作用更强。此外，IT-066的预孵育在广泛洗涤后很长时间内具有显著的免疫效应。多聚甲醛固定的细胞钝化的抑制与IT-066预孵育诱导的β-D13 β-D1 H噻替丁结合，但不与法莫替丁或雷尼替丁预孵育。IT-066对HH 2 R具有强效和持久的拮抗作用。IT-066结合位点中至少有一个不与法莫替丁、雷尼替丁或噻替丁共享，并且受多聚甲醛影响。利用表达HH 2 R的CHO细胞，我们还分析了N-α-甲基组胺（NMeH）对cAMP产生的影响。NMeH是一种H2受体激动剂，由胃粘膜中的H.pyroli产生。NMeH在cAMP产生方面比组胺更有效。虽然NMeH通过H_3受体抑制酸分泌，但它可能通过H_2受体刺激酸分泌。