Inhibitions of acid secretion by E3810 and omeprazole, and their reversal by glutathione.
A substituted benzimidazole ([4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl)- 1H-benzimidazole sodium salt (E3810), is a gastric proton pump (H+, K(+)-ATPase) inhibitor. E3810 and omeprazole inhibited acid accumulation dose dependently as measured with aminopyrine uptake in isolated rabbit gastric glands, their IC50 values being 0.16 and 0.36 microM, respectively. The addition of exogenous reduced glutathione (GSH) to the gland suspension reactivated dose dependently the acid secretion which had been inhibited by 2 microM E3810 or omeprazole as a function of the incubation time. Furthermore, GSH at 1 and 3 mM reversed the antisecretory effect of E3810 more quickly than it did that of omeprazole. The antisecretory effect of E3810 was slightly greater than that of omeprazole in histamine-stimulated fistula dogs in vivo. The duration of the antisecretory activity of E3810 at concentrations of 2 and 4 mg/kg was shorter than that of omeprazole at the same concentrations in pentagastrin-stimulated fistula dogs. The reversal of the antisecretory activity of the inhibitors in dogs is suggested to be due to the action of endogenous extracellular GSH, in addition to de novo synthesis of the proton pump, because bullfrog gastric mucosae were found in the present study to secrete GSH into the mucosal solution at the rate of about 0.25 nmol/min/g tissue.
Fujisaki
H
H
Tsukuba Research Laboratories, Eisai Co., Ltd, Japan.
Shibata
H
H
Oketani
K
K
Murakami
M
M
Fujimoto
M
M
Wakabayashi
T
T
Yamatsu
I
I
Yamaguchi
M
M
Sakai
H
H
Takeguchi
N
N
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D017506:H(+)-K(+)-Exchanging ATPase; D006632:Histamine / Q000494:pharmacology; D008297:Male; D009853:Omeprazole / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010295:Parietal Cells, Gastric / Q000187:drug effects; D010418:Pentagastrin / Q000494:pharmacology; D011817:Rabbits; D064750:Rabeprazole; D011892:Rana catesbeiana
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D000632:Aminopyrine; D064750:Rabeprazole; D003994:Bucladesine; D006632:Histamine; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D010418:Pentagastrin; D005978:Glutathione; D009853:Omeprazole