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HORMONES AND SIGNALING

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

¹Department of Surgery and ²Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Conneticut; and ³AstraZeneca, Mölndal, Sweden

Submitted 16 March 2006 ; accepted in final form 31 May 2006

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.

potassium competitive acid blockers; gastric acid secretion; pH measurements; gastroesophageal reflux disease