title: Characteristics of the K+-competitive H+,K+-ATPase inhibitor AZD0865 in isolated rat gastric glands.
abstract: The gastric H+,K+-ATPase of the parietal cell is responsible for acid secretion in the stomach and is the main target in the pharmacological treatment of acid-related diseases. Omeprazole and other benzimidazole drugs, although having delayed efficacy if taken orally, have high success rates in the treatment of peptic ulcer disease. Potassium competitive acid blockers (P-CAB) compete with K+ for binding to the H+,K+-ATPase and thereby they inhibit acid secretion. In this study, the in vitro properties of AZD0865, a reversible H+,K+-ATPase inhibitor of gastric acid secretion, are described. We used a digital-imaging system and the pH sensitive dye BCECF to observe proton efflux from hand-dissected rat gastric glands. Glands were stimulated with histamine (100 microM) and exposed to a bicarbonate- and Na+-free perfusate to induce an acid load. H+,K+-ATPase inhibition was determined by calculating pHi recovery (dpH/dT) in the presence of omeprazole (10-200 microM) or AZD0865 (0.01-100 microM). The efficacies of both drugs were compared. Our data show that acid secretion is inhibited by both the proton pump inhibitor omeprazole and the P-CAB AZD0865. Complete inhibition of acid secretion by AZD0865 had a rapid onset of activation, was reversible, and occurred at a 100-fold lower dose than omeprazole (1 microM AZD0865 vs. 100 microM omeprazole). This study demonstrates that AZD0865 is a potent, fast-acting inhibitor of gastric acid secretion, effective at lower concentrations than drugs of the benzimidazole class. Therefore, these data strongly suggest that AZD0865 has great potential as a fast-acting, low-dose inhibitor of acid secretion.
authors.affiliation: Department of Surgery, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kirchhoff
authors.forename: K
authors.initials: K
authors.lastname: Andersson
authors.forename: T
authors.initials: T
authors.lastname: Socrates
authors.forename: S
authors.initials: S
authors.lastname: Sidani
authors.forename: O
authors.initials: O
authors.lastname: Kosiek
authors.forename: J P
authors.initials: JP
authors.lastname: Geibel
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003952:Diagnostic Imaging; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009853:Omeprazole / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology*; D054328:Proton Pump Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C514958:AZD0865; D004791:Enzyme Inhibitors; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011725:Pyridines; C035235:Sch 28080; D006632:Histamine; D009853:Omeprazole; D011188:Potassium