Pharmacological regulation of gastric acid secretion in the apical membrane of parietal cells; a new target for antisecretory drugs.
We examined the local effect of several drugs against secretagogue-stimulated acid secretion in dogs. Test drugs were applied to denervated gastric pouches in conscious dogs either for 5 to 30 min beginning 1 hr after or for 30 min before intravenous infusion of gastric secretagogues (histamine, pentagastrin, or carbachol). The antisecretory effect of test drugs delivered by an intravenous or oral route was also examined. Local application of acid pump inhibitors (omeprazole, leminoprazole) for 30 min beginning 1 hr after histamine infusion significantly inhibited gastric acid secretion. The effect of leminoprazole persisted for more than 8 hr after a 30 min application. A mast cell stabilizer (FPL 52694) applied to pouches for 15 to 30 min also potently inhibited histamine-stimulated gastric acid secretion in a time-dependent manner. The duration of the antisecretory effect of such drugs after a 30 min application was greater than 4 hr. Locally applied leminoprazole and FPL 52694 for 30 min also significantly inhibited pentagastrin- and carbachol-stimulated gastric acid secretion. Although intravenous omeprazole and leminoprazole exerted a potent antisecretory effect on histamine-induced acid secretion FPL 52694 had little or no antisecretory effect following intravenous or oral administration. 16,16-dimethyl prostagladin E2 also locally inhibited histamine-stimulated acid secretion. Acid stable local anesthetics (tetracaine, ethyl-4-aminobenzoate), histamine H2-receptor blockers (cimetidine, ranitidine, and famotidine), and a muscarinic M1-receptor antagonist (pirenzepine) did not exhibit local antisecretory effects. Such results strongly suggest that the apical membrane of parietal cells possesses a pharmcologically sensitive portion similar to the basolateral membrane, which usually mediates gastric acid secretion. The apical membrane represents an intriguing target for new antisecretory drugs, as well as a new medium for further elucidating the functional features of parietal cells.
Okabe
S
S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Yamashina, Japan. okabe@mb.kyoto-phu.ac.jp
Shimosako
K
K
Amagase
K
K
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D002867:Chromones; C106473:ME 3407; D011725:Pyridines; D013844:Thiazoles; C029061:FPL-52694; C089751:leminoprazole; D009853:Omeprazole