Effects of a new benzimidazole derivative, NC-1300-O-3, on gastric secretion and gastroduodenal lesions in rats.
We examined the effects of a new compound, NC-1300-O-3 (2-[2-N-methyl-N-(2-methylpropyl) amino] benzylsulfinyl benzimidazole), on the gastric mucosal proton pump (H+, K(+)-ATPase) activity, gastric secretion and gastroduodenal lesions in rats. The compound potently inhibited the enzyme activity in a concentration-dependent manner, the IC50 being 5.3 x 10(-6) M at pH 6.0 and 1.4 x 10(-5) M at pH 7.4. NC-1300-O-3 markedly and persistently (for more than 24 hr) inhibited basal gastric secretion in male or female animals when administered by the p.o. route. The compound also significantly inhibited gastric secretion by the intraduodenal (i.d.), intragastric (after pylorus ligation) and i.p. routes, but only weakly by the s.c. route. Repeated p.o. administration of the compound for 1 week also significantly inhibited gastric secretion. Histamine-stimulated gastric secretion was also significantly inhibited by the i.d. administration of the compound. NC-1300-O-3, administered p.o., potently prevented water-immersion stress-, histamine-, indomethacin-, prednisolone- and compound 48/80-induced gastric lesions. In addition, it also significantly prevented the formation of gastric lesions induced by various necrotizing agents. Mepirizole- and cysteamine-induced duodenal ulcers were also prevented by the compound. The antisecretory and antilesion activities of NC-1300-O-3, administrated p.o., were not altered on its combination with 2% NaHCO3.
Okabe
S
S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Japan.
Akimoto
Y
Y
Yamasaki
S
S
Kuwahara
K
K
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D004285:Dogs; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D007101:Immersion; D066298:In Vitro Techniques; D007213:Indomethacin; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy*; D013315:Stress, Psychological / Q000503:physiopathology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; C048733:2-((2-dimethylaminobenzyl)sulfinyl)benzimidazole; D006632:Histamine; D000251:Adenosine Triphosphatases; D009853:Omeprazole; D007213:Indomethacin