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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Regulation of Somatostatin Release by Adenosine in the Mouse Stomach

Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada (G.K.Y., T.J.K., Y.N.K.); and Department of Neurology, Boston University School of Medicine, Boston, Massachusetts (J.-F.C.)

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 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 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 A_2A receptor knockout (A_2AR-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 A_2AR-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 A₁ receptor, whereas A_2B and A₃ receptors have a minimal role.

Address correspondence to: Yin Nam Kwok, D. H. Copp Building, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. E-mail: kynkwok{at}interchange.ubc.ca