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In the present study, we screened compound libraries to identify inhibitors of the A<jats:sub>2B<\/jats:sub> receptor and evaluated their effect on adenosine-induced intestinal fluid secretion. The screening identified the dihydropyridine calcium antagonists nifedipine and nisoldipine. Their respective affinities for the A<jats:sub>2B<\/jats:sub> receptor (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> value) were 886 and 1,399\u2009nM. Nifedipine and nisoldipine, but not amlodipine or nitrendipine, inhibited both calcium mobilization and adenosine-induced cAMP accumulation in cell lines. Moreover, adenosine injection into the lumen significantly increased fluid volume in the colonic loop of wild-type mice but not A<jats:sub>2B<\/jats:sub> receptor-deficient mice. PSB-1115, a selective A<jats:sub>2B<\/jats:sub> receptor antagonist, and nifedipine prevented elevated adenosine-stimulated fluid secretion in mice. 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