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Glucocorticoids Induce Gastroparesis in Mice Through Depletion of l-Arginine
- Source :
- Endocrinology. 155:3899-3908
- Publication Year :
- 2014
- Publisher :
- The Endocrine Society, 2014.
-
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 GRdim 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.
- Subjects :
- medicine.medical_specialty
Gastroparesis
Gastric motility
Mice, Transgenic
Biology
Arginine
Dexamethasone
Gene Expression Regulation, Enzymologic
Nitric oxide
Mice
03 medical and health sciences
chemistry.chemical_compound
Receptors, Glucocorticoid
0302 clinical medicine
Endocrinology
Internal medicine
medicine
Animals
Glucocorticoids
ARG2
030304 developmental biology
Mice, Inbred BALB C
0303 health sciences
Arginase
Stomach
medicine.disease
Up-Regulation
3. Good health
Mice, Inbred C57BL
medicine.anatomical_structure
chemistry
Gastric acid
Female
hormones, hormone substitutes, and hormone antagonists
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 19457170 and 00137227
- Volume :
- 155
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....2731ab259f674fac2e8fc9a0207189d2