Effects of NC-1300-B, a new benzimidazole derivative, on hog gastric H+, K+-ATPase, gastric acid secretion and HCl.ethanol-induced gastric lesions in rats.
This study was designed to determine the effect of a newly synthesized benzimidazole derivative NC-1300-B on H+, K+-ATPase (proton pump) in the hog gastric mucosa and on the basal gastric acid secretion and necrotizing agent-induced gastric lesions in rats. NC-1300-B inhibited the proton pump in a concentration-dependent manner and concentrations which inhibited the enzyme activity by 50% were 4.4 x 10(-6) M at pH 6.0 and 3.1 x 10(-5) M at pH 7.4. NC-1300-B administered orally or intraperitoneally 0.5 hr before ligating the pylorus inhibited the gastric acid secretion in a dose-dependent manner. The ED50 values (doses which inhibit acid output or lesion formation by 50%) for acid secretion were 11.5 and 11.0 mg/kg with oral and intraperitoneal administration, respectively. The antisecretory effect in a dose of 100 mg/kg persisted for up to 72 hr. NC-1300-B administered orally or intraperitoneally 0.5 hr before HCl.ethanol administration protected against damage of the gastric mucosa in a dose-dependent manner. The ED50 values for lesion formation were 13.3 and 23.0 mg/kg with oral and intraperitoneal administration, respectively. This protection with an oral dose of 100 mg/kg persisted for up to 72 hr. While pretreatment with 5 mg/kg of indomethacin given subcutaneously did not appreciably reverse the NC-1300-B protection, the pretreatment with 10 mg/kg of N-ethylmaleimide given subcutaneously potently reversed the NC-1300-B protection. NC-1300-B administered intragastrically at 30 mg/kg significantly inhibited the amplitude of gastric contraction for 50 min after intragastric administration. These effects of NC-1300-B on gastric secretion and lesion formation are much the same as those of the established proton pump inhibitor omeprazole, except for the short duration of the action of omeprazole (less than 24 hr).
Okabe
S
S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Japan.
Akimoto
Y
Y
Yamasaki
S
S
Nagai
H
H
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine
D001562:Benzimidazoles; C057696:NC 1300 B; D000431:Ethanol; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole