Glucocorticoids Induce Gastroparesis in Mice Through Depletion of l-Arginine

• DOI: 10.1210/en.2014-1246
• Publication Date: 2014-07-24T14:39:44Z
• Authors: Sybille D. Reichardt; Toni Weinhage; Anand Rotte; Michael Föller; Martin Oppermann; Fred Lühder; Jan P. Tuckermann; Florian Lang; Jens van den Brandt; Holger M. Reichardt
• Keywords: Gastroparesis

Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment inflammatory diseases. In our search for new mechanisms action, we identified hitherto unknown effect GCs gastrointestinal tract. We found that oral administration dexamethasone (Dex) to mice caused an enlargement stomach due induction gastroparesis and this was abolished GR(dim) carrying A458T mutation GC receptor (GR). Gastroparesis unrelated enhanced gastric acid secretion observed after Dex treatment, although both effects were mediated by same molecular mechanism GR. Using conditional GR-knockout mice, could further rule out on enterocytes or myeloid cells involved gastroparesis. contrast, upregulated arginase 2 (Arg2) at mRNA protein level. This suggests leads depletion l-arginine thereby impeding production nitric oxide (NO), which is required motility. tested hypothesis supplementing drinking water with exogenous compensate presumed shortage major substrate NO synthases. Importantly, measure completely prevented treatment. Our findings raise considerations combining orally applied improve tolerability provide possible explanation antiemetic widely exploited chemotherapy.