PI3 kinase dependent stimulation of gastric acid secretion by dexamethasone.
Excessive gastric acid secretion plays an important role in the pathogenesis of peptic ulcers. Dexamethasone, a widely used drug, is known to stimulate gastric acid secretion and increase the incidence of peptic ulcers. However little is known about the mechanism of the dexamethasone's effect on parietal cells. The present study was performed to investigate the contribution of the phosphatidylinositol-3-kinase (PI3 kinase) to dexamethasone induced stimulation of gastric acid secretion. In vivo pretreatment with dexamethasone injections (150 microg/100g for 3 days) or in vitro exposure to (10 microM for > 20 minutes) significantly increased acid secretion in isolated gastric glands approximately 2-3 fold. The dexamethasone induced stimulation of gastric acid secretion was concentration dependent and significantly blunted by the H+/K2+ ATPase inhibitor omeprazole (200 microM), the PI3 kinase inhibitor Wortmannin (500 nM), the protein kinase inhibitor staurosporine (2.5 microM) and the Cl(-) channel blocker NPPB (100 microM); but not by the H(2) antagonist cimetidine (100 microM). In conclusion, it was observed that dexamethasone's effect on proton extrusion requires the activity of a PI3 kinase pathway, an apical Cl(-) channel and the H2+/K2+ ATPase.
Lang
Philipp A
PA
Department of Surgery, School of Medicine, Yale University, New Haven, CT 06520-8026, USA.
Schniepp
Roman
R
Kirchhoff
Philipp
P
Socrates
Thenral
T
Sidani
Shafik M
SM
Geibel
John P
JP
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D008297:Male; D009579:Nitrobenzoates / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002927:Cimetidine; D003907:Dexamethasone; D017506:H(+)-K(+)-Exchanging ATPase; D009579:Nitrobenzoates; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D019311:Staurosporine; D000077191:Wortmannin; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid