Regulation of Somatostatin Release by Adenosine in the Mouse Stomach

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 >or= 1.0 microM stimulated gastric release of somatostatin-like immunoreactivity (SLI), and this effect was blocked by the A(2A) 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 A(2A) receptor agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride] augmented SLI release in a concentration-dependent manner, suggesting that A(2A) receptor activation is involved in the stimulatory effect of adenosine on SLI release. Conversely, SLI release was inhibited by the A(1) receptor agonists N(6)-cyclopentyladenosine and 2-chloro-N(6)-cyclopentyladenosine and lower concentration of adenosine (0.01 microM). The involvement of specific adenosine receptors in controlling the release of gastric SLI was also examined using A(2A) receptor knockout (A(2A)R-KO) mice. In these mice, adenosine (10 microM) inhibited SLI release, and the effect was abolished by the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, suggesting a link between the selective A(1) 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 A(2A)R-KO mice. We conclude that adenosine has dual actions on regulating mouse gastric SLI release: stimulatory at higher concentrations through the A(2A) receptor and inhibitory at lower concentrations through the A(1) receptor, whereas A(2B) and A(3) receptors have a minimal role.