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

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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.

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Abbreviations

CCK-2R:

Type 2 receptor of cholecystokinin/gastrin

CckbR:

Rat gene coding type 2 receptor of cholecystokinin

CV:

Intraassay coefficient of variation

ECL:

Enterochromaffin-like (cell)

Gast :

Rat gastrin gene

Ghrl :

Rat ghrelin gene

GhsR:

Rat ghrelin receptor

H2RA:

Histamine H2 receptor antagonist

HPRT1:

Gene coding hypoxanthine-guanine phosphoribosyltransferase

iNOS:

Inducible nitric oxide synthase (i.e., expressed protein possessing enzymatic activity)

NOS2:

Gene coding iNOS

IV:

Intravenous

NSAID:

Nonsteroidal antiinflammatory drug

PPI:

Proton pump inhibitor

qPCR:

Quantitative polymerase reaction

SstR2:

Rat gene coding type 2 receptor of somatostatin

Sst:

Rat somatostatin gene

SC:

Subcutaneous

YF476:

(R)-1-[2,3-Dihydro-2-oxo-1-pivaloylmethyl-5-(2-pyri-dyl)-1H-1,4-benzo-diazepin-3-yl]-3-(3-methylaminophenyl)urea

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Acknowledgments

This study was funded by GlaxoSmithKline and supported by Karolinska Institutet and Uppsala University. D-L Webb gratefully acknowledges grants from Bengt Ihres Foundation and Socialstyrelsen.

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Authors and Affiliations

  1. Department of Medical Sciences, Gastroenterology & Hepatology unit, Building 40, Uppsala University, 751 85, Uppsala, Sweden

    Dominic-Luc Webb, Tobias Rudholm-Feldreich, Md. Abdul Halim & Per M. Hellström

  2. Department of Medicine and Gastroenterology & Hepatology Unit, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden

    Linda Gillberg

  3. Clinical Chemistry, Linköping University, Linköping, Sweden

    Elvar Theodorsson

  4. Blizard Institute, Neurogastroenterology group, Queen Mary, University of London, Harlow, UK

    Gareth J. Sanger

  5. Neurology & GI CEDD, GlaxoSmithKline, Harlow, UK

    Colin A. Campbell

  6. Hammersmith Medicines Research, London, UK

    Malcolm Boyce

  7. Department of Clinical Sciences, Surgery Unit, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden

    Erik Näslund

Authors
  1. Dominic-Luc Webb
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  2. Tobias Rudholm-Feldreich
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  3. Linda Gillberg
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  4. Md. Abdul Halim
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  5. Elvar Theodorsson
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  6. Gareth J. Sanger
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  7. Colin A. Campbell
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  8. Malcolm Boyce
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  9. Erik Näslund
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  10. Per M. Hellström
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Correspondence to Per M. Hellström.

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Dominic-Luc Webb and Tobias Rudholm-Feldreich contributed equally.

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Webb, DL., Rudholm-Feldreich, T., Gillberg, L. et al. The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression. Naunyn-Schmiedeberg's Arch Pharmacol 386, 41–49 (2013). https://doi.org/10.1007/s00210-012-0812-5

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  • DOI: https://doi.org/10.1007/s00210-012-0812-5

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