Characteristics of the K+-competitive H+,K+-ATPase inhibitor AZD0865 in isolated rat gastric glands.

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 µM) and exposed to a bicarbonate- and Na⁺-free perfusate to induce an acid load. H⁺,K⁺-ATPase inhibition was determined by calculating pH_i recovery (dpH/dT) in the presence of omeprazole (10-200 µM) or AZD0865 (0.01-100 µM). 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 µM AZD0865 vs. 100 µM 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. [ABSTRACT FROM AUTHOR]