A_2B adenosine receptor inhibition by the dihydropyridine calcium channel blocker nifedipine involves colonic fluid...

The adenosine A_2B receptor is a critical protein in intestinal water secretion. In the present study, we screened compound libraries to identify inhibitors of the A_2B 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_2B receptor (K_i value) were 886 and 1,399 nM. 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_2B receptor-deficient mice. PSB-1115, a selective A_2B receptor antagonist, and nifedipine prevented elevated adenosine-stimulated fluid secretion in mice. Our results may provide useful insights into the structure-activity relationship of dihydropyridines for A_2B receptor. As colonic fluid secretion by adenosine seems to rely predominantly on the A_2B receptor, nifedipine could be a therapeutic candidate for diarrhoea-related diseases.