title: Glucocorticoids induce gastroparesis in mice through depletion of l-arginine.
abstract: Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment of inflammatory diseases. In our search for new mechanisms of action, we identified a hitherto unknown effect of GCs in the gastrointestinal tract. We found that oral administration of dexamethasone (Dex) to mice caused an enlargement of the stomach due to the induction of gastroparesis and that this effect was abolished in GR(dim) mice carrying the A458T mutation in the GC receptor (GR). Gastroparesis was unrelated to the enhanced gastric acid secretion observed after Dex treatment, although both effects were mediated by the same molecular mechanism of the GR. Using conditional GR-knockout mice, we could further rule out that GC effects on enterocytes or myeloid cells were involved in the induction of gastroparesis. In contrast, we found that Dex upregulated arginase 2 (Arg2) in the stomach both at the mRNA and protein level. This suggests that GC treatment leads to a depletion of l-arginine thereby impeding the production of nitric oxide (NO), which is required for gastric motility. We tested this hypothesis by supplementing the drinking water of the mice with exogenous l-arginine to compensate for the presumed shortage of this major substrate of NO synthases. Importantly, this measure completely prevented both the enlargement of the stomach and the induction of gastroparesis after Dex treatment. Our findings raise considerations of combining orally applied GCs with l-arginine to improve tolerability of GC treatment and provide a possible explanation for the antiemetic effects of GCs widely exploited in chemotherapy.
authors: Institute for Cellular and Molecular Immunology (S.D.R., T.W., M.O., J.v.d.B., H.M.R.) and Department of Neuroimmunology (F.L.), Institute for Multiple Sclerosis Research, The Hertie Foundation and MPI for Experimental Medicine, University of Göttingen Medical School, 37073 Göttingen, Germany; Institute of Physiology (A.R., M.F., F.L.), University of Tübingen, 72076 Tübingen, Germany; and Institute of General Zoology and Endocrinology (J.P.T.), University of Ulm, 89081 Ulm, Germany.
authors: Sybille D
authors: SD
authors: Reichardt
authors: Toni
authors: T
authors: Weinhage
authors: Anand
authors: A
authors: Rotte
authors: Michael
authors: M
authors: Föller
authors: Martin
authors: M
authors: Oppermann
authors: Fred
authors: F
authors: Lühder
authors: Jan P
authors: JP
authors: Tuckermann
authors: Florian
authors: F
authors: Lang
authors: Jens
authors: J
authors: van den Brandt
authors: Holger M
authors: HM
authors: Reichardt
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000172:deficiency*; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D018589:Gastroparesis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D001120:Arginine; C481673:Arg2 protein, mouse; D001119:Arginase