Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid receptors.
Excess glucocorticoids result in decreased aortic dilation and expression of guanosine triphosphate (GTP) cyclohydrolase 1 (GTPCH1) messenger RNA (mRNA), the rate-limiting enzyme in the production of the nitric oxide synthase (NOS) cofactor tetrahydrobiopterin (BH4). It was hypothesized that this response is a genomic effect mediated through the glucocorticoid receptor (GR). Endothelium-intact rat aortas were incubated with dexamethasone (DEX; 1.3 x 10(-6) M) or vehicle for 2 or 6 hours and isometric force generation was measured. Maximum acetylcholine-induced relaxation in DEX-2hr aortas was not different compared with control values; however, acetylcholine-induced relaxations in DEX-6hr aortas were significantly decreased. Coincubation with sepiapterin (10(-4) M), which produces BH4 via a salvage pathway, restored relaxation in DEX-6hr aortas to that of controls. Coincubation with the GR antagonist mifepristone (10(-6) M) completely blocked the DEX-induced decrease in relaxation. Spironolactone (10(-5) M), a mineralocorticoid receptor antagonist, had no effect. GTPCH1 mRNA expression was significantly decreased in DEX-6hr aortas compared with control values. This was blocked by mifepristone; however, spironolactone and cycloheximide did not prevent the decrease of GTPCH1 by DEX. These results support the hypothesis that GTPCH1 downregulation by glucocorticoids is mediated through the GR and contributes to reduced endothelium-dependent relaxation.
Mitchell
Brett M
BM
Department of Physiology, Medical College of Georgia, Augusta, 30912, USA. bretmitchell@hotmail.com
Dorrance
Anne M
AM
Mack
Eniki A
EA
Webb
R Clinton
RC
D000818:Animals; D001013:Aorta, Thoracic; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects; D006136:GTP Cyclohydrolase / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation / Q000187:drug effects*
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D001708:Biopterins; D003907:Dexamethasone; D006136:GTP Cyclohydrolase; C003402:sapropterin