Abstract
The adenosine A2B receptor is a critical protein in intestinal water secretion. In the present study, we screened compound libraries to identify inhibitors of the A2B 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 A2B receptor (Ki 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 A2B receptor-deficient mice. PSB-1115, a selective A2B 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 A2B receptor. As colonic fluid secretion by adenosine seems to rely predominantly on the A2B receptor, nifedipine could be a therapeutic candidate for diarrhoea-related diseases.
Highlights
The adenosine A2B receptor is a critical protein in intestinal water secretion
Three were already known, four had a xanthine-like structure, and two were dihydropyridine calcium channel blockers. We focused on the latter, nifedipine and nisoldipine, because dihydropyridine is similar to the structure of BAY60-6583, a known adenosine A2B receptor agonist (Fig. 1)
We confirmed the effect of nifedipine on adenosine-induced calcium mobilization in Chinese hamster ovary (CHO) cells stably expressing the A2B receptor
Summary
We screened compound libraries to identify inhibitors of the A2B receptor and evaluated their effect on adenosine-induced intestinal fluid secretion. As colonic fluid secretion by adenosine seems to rely predominantly on the A2B receptor, nifedipine could be a therapeutic candidate for diarrhoea-related diseases. The activated A2B receptor stimulates intestinal water secretion and sensation or modulates inflammatory response and colonic motility[5,6]. As a result, it is associated with the development of gastrointestinal diseases, such as irritable bowel syndrome (IBS), secretary diarrhoea, and inflammatory bowel disease[7,8]. We determined the role of various adenosine receptor subtypes involved in colonic fluid secretion induced by luminal adenosine and examined the effect of the candidate drug on fluid secretion in mice
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