Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function.
Tetrahydrobiopterin (BH4) acts as an important co-factor for endothelial nitric oxide synthase (eNOS). Glucocorticoids have been shown to inhibit expression of the rate-limiting enzyme for tetrahydrobiopterin synthesis, GTP cyclohydrolase, in other cell types. We hypothesized that endothelium-dependent vasodilator responses would be blunted in rats made hypertensive with dexamethasone. Further, we hypothesized that treatment of rat vascular segments with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression. We report that endothelium-dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone-hypertensive rats compared with sham values. Dexamethasone incubation abolishes contraction to Nomega-nitro-L-arginine (L-NNA, 10(-5) M) in endothelium-intact aortic rings, and inhibits expression of GTP cyclohydrolase. We conclude that inhibition of BH4 synthesis by glucocorticoid regulation of GTP cyclohydrolase expression may contribute to reduced endothelium-dependent vasodilation characteristic of glucocorticoid-induced hypertension.
Johns
D G
DG
Department of Physiology, Medical College of Georgia, Augusta 30912-3000, USA.
Dorrance
A M
AM
Tramontini
N L
NL
Webb
R C
RC
D000818:Animals; D001013:Aorta, Thoracic; D001708:Biopterins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine; D010656:Phenylephrine; D011621:Pteridines; D011622:Pterins; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects*
D005938:Glucocorticoids; D011621:Pteridines; D011622:Pterins; D010656:Phenylephrine; D019335:Nitroarginine; D001708:Biopterins; D003907:Dexamethasone; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006136:GTP Cyclohydrolase; C003402:sapropterin