Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice.
To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. fukusima-tky@umin.ac.jp
Yasushi
Y
Fukushima
Takayuki
T
Shindo
Motonobu
M
Anai
Toshihito
T
Saitoh
Yuhui
Y
Wang
Midori
M
Fujishiro
Yoshio
Y
Ohashi
Takehide
T
Ogihara
Kouichi
K
Inukai
Hiraku
H
Ono
Hideyuki
H
Sakoda
Yukiko
Y
Kurihara
Miho
M
Honda
Nobuhiro
N
Shojima
Harumi
H
Fukushima
Yukiko
Y
Haraikawa-Onishi
Hideki
H
Katagiri
Yasuhito
Y
Shimizu
Masao
M
Ichinose
Takashi
T
Ishikawa
Masao
M
Omata
Ryozo
R
Nagai
Hiroki
H
Kurihara
Tomoichiro
T
Asano
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D015152:Blotting, Northern; D004597:Electroshock; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005755:Gastrins / Q000097:blood; D018390:Gene Targeting; D006863:Hydrogen-Ion Concentration; D006965:Hyperplasia; D007150:Immunohistochemistry; D064747:Lansoprazole; D051379:Mice; D009853:Omeprazole / Q000031:analogs & derivatives / Q000494:pharmacology; D017288:Pain Threshold; D054328:Proton Pump Inhibitors; D011970:Receptors, Histamine H2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D005755:Gastrins; D054328:Proton Pump Inhibitors; D011970:Receptors, Histamine H2; D064747:Lansoprazole; D009853:Omeprazole