title: Dexamethasone suppresses eNOS and CAT-1 and induces oxidative stress in mouse resistance arterioles.
abstract: Long-term treatment with glucocorticoids is associated with mild to moderate hypertension. We reported previously that downregulation of endothelial NO synthase (eNOS) expression and activity is likely to contribute to this increase in blood pressure. In the present study, we tested the effects of dexamethasone on the vasodilation of microvascular arterioles using implanted dorsal skin-fold chambers in anesthetized C57BL/6J mice. Experiments were performed on control mice or on mice treated with dexamethasone (0.1-3 mg/kg of body wt). Endothelium-dependent vasodilation in response to ACh (0.1-10 microM) was reduced by dexamethasone in a dose-dependent fashion. Comparable inhibition was seen in tissues superfused with 30 microM N(G)-nitro-L-arginine methyl ester. In contrast, endothelium-independent vasodilation in response to S-nitroso-N-acetyl-D,L-penicillamine (10 microM) was not influenced by either dexamethasone or N(G)-nitro-L-arginine methyl ester. Levels of eNOS mRNA in murine hearts and NO(2)(-)/NO(3)(-) in serum were suppressed by dexamethasone (down to 63 and 50% of control values, respectively, at 3 mg/kg of body wt) along with a reduction in eNOS protein to 85.6%. Dexamethasone also concentration dependently reduced the expression of the cationic amino acid transporter-1 in murine hearts and cultured endothelial cells. The suppression by dexamethasone of the ACh-induced vasodilation could be partially reversed by dietary L-arginine (50 mg/kg of body wt) and by dietary vitamin C (10 g/kg of diet). We conclude that suppression by dexamethasone of the endothelium-mediated microvascular vasodilation involves several mechanisms including 1) downregulation of eNOS, 2) downregulation of cationic amino acid transporter-1, and 3) generation of reactive oxygen species. The demonstration that L-arginine and vitamin C can partially offset the effects of dexamethasone on microvascular arterioles suggests the potential clinical usefulness of these agents for the reduction of glucocorticoid-induced hypertension.
authors.affiliation: Department of Pathology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: S C
authors.initials: SC
authors.lastname: Schäfer
authors.forename: T
authors.initials: T
authors.lastname: Wallerath
authors.forename: E I
authors.initials: EI
authors.lastname: Closs
authors.forename: C
authors.initials: C
authors.lastname: Schmidt
authors.forename: P M
authors.initials: PM
authors.lastname: Schwarz
authors.forename: U
authors.initials: U
authors.lastname: Förstermann
authors.forename: H-A
authors.initials: HA
authors.lastname: Lehr
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001205:Ascorbic Acid / Q000494:pharmacology; D027201:Cationic Amino Acid Transporter 1 / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000037:antagonists & inhibitors / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000037:antagonists & inhibitors / Q000097:blood; D018384:Oxidative Stress / Q000502:physiology; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000975:Antioxidants; D027201:Cationic Amino Acid Transporter 1; D005938:Glucocorticoids; D009566:Nitrates; D009573:Nitrites; C420826:Slc7a1 protein, mouse; D003907:Dexamethasone; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000109:Acetylcholine; D001205:Ascorbic Acid