title: Antisecretory and antilesional effect of a new histamine H2-receptor antagonist, IT-066, in rats.
abstract: The effects of a new histamine H2-receptor antagonist, IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-++ +butenylamino]- 3-cyclobutene-1,2-dione hydrochloride), were investigated on the secretagogue-induced acid secretion in vivo and in vitro, and on experimental gastric and duodenal lesion in rats. IT-066 (10-60 micrograms/kg) given i.v. inhibited histamine-stimulated acid secretion dose-dependently in gastric lumen-perfused rats, and the inhibitory effect was observed for about 12 hr. Famotidine (FMD) (10-60 micrograms/kg i.v.) also had an antisecretory effect, but the acid secretion recovered to the control level 4 hr after the administration. Cold stress plus indomethacin-induced lesion was significantly inhibited by IT-066 and FMD given i.v. 30 min before the cold stress plus indomethacin treatment. IT-066 given 7 hr before the cold stress plus indomethacin treatment also inhibited lesion formation significantly, but such antilesional effect was not observed with FMD. In the rat isolated gastric mucosal sheet, IT-066 inhibited histamine-stimulated acid secretion dose-dependently and noncompetitively; its action was produced via a unique mechanism. The inhibitory effect of IT-066 remained after washing of the mucosa, and became more potent time-dependently. The inhibitory effects of FMD and cimetidine were not observed after washing the mucosa. These data suggest that IT-066 has a potent and long lasting antisecretory effect in vivo and in vitro, and that these properties are responsible for the long lasting antilesional action.
authors.affiliation: Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saltama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Isobe
authors.forename: H
authors.initials: H
authors.lastname: Nagai
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.forename: H
authors.initials: H
authors.lastname: Aihara
authors.forename: S
authors.initials: S
authors.lastname: Otomo
mesh_terms: D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003080:Cold Temperature; D003543:Cysteamine; D004305:Dose-Response Relationship, Drug; D004379:Duodenal Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D015738:Famotidine / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007213:Indomethacin; D008297:Male; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C063924:IT 066; D015738:Famotidine; D003543:Cysteamine; D002927:Cimetidine; D007213:Indomethacin