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 H₂ receptor, histamine H₂ receptor-null mice were generated by homologous recombination. Histamine H₂ 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 H₂ receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H₂ receptor-null mice, gastric pH was elevated by both muscarinic M₃ and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H₂ 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 H₂ 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 H₂ receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H₂ receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H₂ receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H₂ 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 H₂ receptor-null mice, (2) abnormal gastric glands in histamine H₂ receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H₂ receptors are functional in the central nervous system.