The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression.

Abstract

YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (±0.06). YF476 raised pH to 3.67 (±0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.

• Authors: Dominic-Luc Webb, Tobias Rudholm-Feldreich, Linda Gillberg, Md Abdul Halim, Elvar Theodorsson, Gareth J Sanger, Colin A Campbell, Malcolm Boyce, Erik Näslund, Per M Hellström
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 386 Issue 1 Pg. 41-9 (Jan 2013) ISSN: 1432-1912 [Electronic] Germany
• PMID: 23179899 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Anti-Ulcer Agents
• Benzodiazepinones
• Phenylurea Compounds
• Receptor, Cholecystokinin B
• Diclofenac
• Nitric Oxide Synthase Type II
• YF 476
• Esomeprazole

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (toxicity)
• Anti-Ulcer Agents (pharmacology)
• Benzodiazepinones (pharmacology)
• Diclofenac (toxicity)
• Esomeprazole (pharmacology)
• Gastric Mucosa (drug effects, pathology)
• Gene Expression Regulation (drug effects)
• Hydrogen-Ion Concentration
• Male
• Nitric Oxide Synthase Type II (genetics)
• Phenylurea Compounds (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cholecystokinin B (antagonists & inhibitors)
• Stomach Ulcer (chemically induced, prevention & control)