Akito Nishida, Ayumi Uchida-Kobayashi, Yukihiro Takemoto, Shinobu Akuzawa and Keiji Miyata
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan
Abstract: We determined the relative contributions of endogenous gastrin, histamine and cholinergic tone to basal acid secretion in chronic fistula rats. Results were compared with those for acid secretion in pylorus-ligated rats. In chronic fistula rats, YM022 {(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo- 5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea} dose-dependently inhibited pentagastrin- stimulated acid secretion and abolished this secretion at 1 micromol/kg, s.c., but did not affect histamine- and carbachol-induced acid secretion even at 10 micromol/kg. In contrast, famotidine at 1 micromol/kg completely inhibited not only the acid secretion induced by histamine but also those by pentagastrin and carbachol. Furthermore, atropine abolished carbachol- and pentagastrin-stimulated acid secretion and significantly suppressed histamine-stimulated acid secretion at 0.1 micromol/kg. YM022 dose-dependently inhibited basal acid secretion. The YM022 dosage required to inhibit basal acid secretion is consistent with that required to suppress pentagastrin-induced acid secretion. Famotidine (1 micromol/kg) and atropine (0.1 micromol/kg) also abolished basal acid secretion. In pylorus-ligated rats, YM022 inhibited acid secretion in a dose-dependent manner; the inhibition at 1 micromol/kg, i.v. was 65%. No additional effect was observed when rats were dosed at 30 micromol/kg. Famotidine partially inhibited acid secretion in these rats, whereas atropine abolished this secretion. These results indicate that the major part of basal acid secretion in rats is attributable to endogenous gastrin via histamine- and cholinergic tone-dependent pathways. Moreover, pylorus ligation reduces the relative contribution of gastrin to acid secretion due to the activation of cholinergic tone.
Keywords:
YM022, Basal acid secretion, Gastrin receptor, Histamine H2-receptor, Cholinergic neuron