A(2B) adenosine receptor inhibition by the dihydropyridine calcium channel blocker nifedipine involves colonic fluid secretion

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.