Antisecretory and antilesional effect of a new histamine H2-receptor antagonist, IT-066, in rats

Y Isobe, H Nagai, M Muramatsu, H Aihara and S Otomo

Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saltama, Japan.

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.

Volume 255, Issue 3, pp. 1078-1082, 12/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics