Abstract
Adenosine has been shown to inhibit immunoreactive gastrin (IRG) release and to stimulate somatostatin-like immunoreactivity (SLI) release by activating adenosine A1 and A2A receptors, respectively. Since the synthesis and release of gastrin and somatostatin are regulated by the acid secretory state of the stomach, the effect of achlorhydria on A1 and A2A receptor gene expression and function was examined. Omeprazole-induced achlorhydria was shown to suppress A1 and A2A receptor gene expression in the antrum and corporeal mucosa, but not in the corporeal muscle. Omeprazole treatment produced reciprocal changes in A1 receptor and gastrin gene expression, and parallel changes in A2A receptor and somatostatin gene expression. The localization of A1 and A2A receptors on gastrinsecreting G-cells and somatostatin-secreting D-cells, respectively, suggests that changes in adenosine receptor expression may modulate the synthesis and release of gastrin and somatostatin. Thus, the effect of omeprazole on adenosine receptor-mediated changes in IRG and SLI release was also examined in the vascularly perfused rat stomach. After omeprazole treatment, the A1 receptor-mediated inhibition of IRG and SLI release induced by N6-cyclopentyladenosine (A1 receptor-selective agonist) was not altered, but the A2A receptor-mediated augmentation of SLI release induced by 2-p-(2-carboxyethyl-)phenethylamino-5′-N-ethylcarboxamidoadenosine (A2A-selective agonist) was significantly attenuated. These findings agree well with the corresponding omeprazole-induced decrease in antral A2A receptor mRNA expression. Overall, the present study suggests that adenosine receptor gene expression and function may be altered by omeprazole treatment. Acid-dependent changes in adenosine receptor expression may represent a novel purinergic regulatory feedback mechanism in controlling gastric acid secretion.
Footnotes
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This work was supported by the Canadian Apoptosis Research Foundation Society, the Canada Foundation for Innovation, the 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.
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A portion of this work was included in Linda Yip's Ph.D. thesis (Yip, 2004). Part of this work was presented at the Purines 2004 meeting (Yip et al., 2004a), and a portion of this work has previously been published in abstract form (Yip and Kwok, 2002).
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doi:10.1124/jpet.104.069708.
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ABBREVIATIONS: IRG, immunoreactive gastrin; CPA, N6-cyclopentyladenosine; CGS 21680, 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine; SLI, somatostatin-like immunoreactivity; RT-PCR, reverse transcription-polymerase chain reaction; RIA, radioimmunoassay; CT, threshold cycle; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ZM 241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance.
- Received April 7, 2004.
- Accepted May 20, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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