Abstract
Adenosine inhibits gastric acid secretion, either directly by acting on acid-secreting parietal cells or indirectly by stimulating the release of the acid inhibitor, somatostatin. The present study examined the role of adenosine on somatostatin release in an isolated vascularly perfused mouse stomach model. Concentrations of exogenous adenosine ≥ 1.0 μM stimulated gastric release of somatostatin-like immunoreactivity (SLI), and this effect was blocked by the A2A receptor antagonist ZM 241385 [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol]. The A2A receptor agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride] augmented SLI release in a concentration-dependent manner, suggesting that A2A receptor activation is involved in the stimulatory effect of adenosine on SLI release. Conversely, SLI release was inhibited by the A1 receptor agonists N6-cyclopentyladenosine and 2-chloro-N6-cyclopentyladenosine and lower concentration of adenosine (0.01 μM). The involvement of specific adenosine receptors in controlling the release of gastric SLI was also examined using A2A receptor knockout (A2AR-KO) mice. In these mice, adenosine (10 μM) inhibited SLI release, and the effect was abolished by the selective A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, suggesting a link between the selective A1 activation and inhibition of SLI release. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride augmented SLI release in wild-type controls but not in the presence of ZM 241385 or in A2AR-KO mice. We conclude that adenosine has dual actions on regulating mouse gastric SLI release: stimulatory at higher concentrations through the A2A receptor and inhibitory at lower concentrations through the A1 receptor, whereas A2B and A3 receptors have a minimal role.
Footnotes
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This work was supported by the Wah Sheung Fund.
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Parts of this work were previously presented at the following conference: Yang GK, Ming G, Kieffer TJ, and Kwok YN (2007) Purinergic control of gastric somatostatin release. Experimental Biology Annual Meeting; 2007 Apr 28–May 2; Washington, DC. FASEB, Bethesda, MD.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.146050.
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ABBREVIATIONS: A2AR-KO, adenosine A2A receptor knockout; CPA, N6-cyclopentyladenosine; CCPA, 2-chloro-N6-cyclopentyladenosine; CGS 21680, 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride; 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; EHNA, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride; ZM 241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol; SLI, somatostatin-like immunoreactivity; ANOVA, analysis of variance; Ado, adenosine.
- Received September 15, 2008.
- Accepted February 9, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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