Abstract
Adenosine has been demonstrated to inhibit gastric acid secretion. In the rat stomach, this inhibitory effect may be mediated indirectly by the inhibition of gastrin release. Results show that the A1 receptor agonist N6-cyclopentyladenosine (CPA) suppressed immunoreactive gastrin (IRG) release in a concentration-dependent manner. CPA significantly inhibited IRG release at 0.001 μM and maximally inhibited IRG release at 1 μM. At concentrations of 0.001 to 0.1 μM, the A2A receptor-selective agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine and A3 receptor-selective agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide, had no effect on IRG release, suggesting the involvement of A1 receptors. In agreement, the A1 receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine abolished adenosine-induced inhibition of IRG release. Results of immunohistochemistry experiments reveal the presence of A1 receptor immunoreactivity on mucosal G-cells and D-cells, and the gastric plexi, but not parietal cells, suggesting that adenosine may act directly on G-cells or indirectly on the gastric plexi to modulate IRG release. The structure of the mucosal A1 receptor was found to be identical to that in the rat brain. Alternative splicing within the coding region of this receptor did not occur. A real-time reverse transcription-polymerase chain reaction assay was developed to measure gastric A1 receptor gene expression. The highest level of gastric A1 receptor mRNA was found in the corporeal muscle. However, this level was significantly lower in comparison with the striatum. In conclusion, this study shows that adenosine may suppress IRG release, at least in part, by activating A1 receptors localized on G-cells and may consequently result in an inhibition of gastric acid secretion.
Footnotes
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This work was supported by the Canadian Apoptosis Research Foundation Society, Canada Foundation for Innovation, Wah Sheung Fund, and the former British Columbia Health Research Foundation. L.Y. was supported by the Cordula and Gunter Paetzold Fellowship and the University of British Columbia Graduate Fellowship. A portion of this work was included in Linda Yip's Ph.D. dissertation entitled Adenosine A1 and A2A Receptors in the Rat Stomach: Biological Actions, Cellular Localization, Structure, and Gene Expression. Citation of meeting abstracts where part of this work was previously presented: Yip L and Kwok YN (2002) Gastric A1 and A2A receptors: cellular localization, gene sequence and gene expression levels. Drug Dev Res56:551 and Yip L, Leung CH, and Kwok YN (2003) Cellular localization of adenosine A1 and A2A receptors in the rat stomach. FASEB J17:A40.
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DOI: 10.1124/jpet.104.066654.
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ABBREVIATIONS: IRG, immunoreactive gastrin; RT-PCR, reverse transcription-polymerase chain reaction; BSA, bovine serum albumin; RIA, radioimmunoassay; CPA, N6-cyclopentyladenosine; CGS 21680, 2-p-(2-carboxyethyl)phenethylamino-5′N-ethylcarboxamidoadenosine; IB-MECA, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; DMPX, 3,7-dimethyl-1-propargylxanthine; A1R-IR, A1 receptor-immunoreactivity; TBS, Tris-buffered saline; TBST, Tris-buffered saline/Tween 20; PBS, phosphate-buffered saline; IR, immunoreactivity; PGP 9.5, protein gene product 9.5; VWF, von Willebrand's factor; bp, base pair(s); SLI, somatostatin-like immunoreactivity.
- Received February 6, 2004.
- Accepted March 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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