title: GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats.
abstract: NO, a potent vasodilator, has been implicated in the pathogenesis of glucocorticoid hypertension. NO synthase requires the cofactor tetrahydrobiopterin for the production of NO. Guanosine-triphosphate (GTP) cyclohydrolase 1 is the rate-limiting enzyme for the production of tetrahydrobiopterin, and in the presence of low levels of tetrahydrobiopterin, NO production is decreased. We have previously shown that tetrahydrobiopterin-dependent vasodilation is impaired in rats with glucocorticoid hypertension. However, the role GTP cyclohydrolase 1 plays in the pathogenesis of glucocorticoid hypertension has not been investigated. Therefore, we tested the hypothesis that downregulation of GTP cyclohydrolase 1 contributes to the development and maintenance of glucocorticoid hypertension in rats. Rats were implanted with dexamethasone (0.79 mg x kg(-1) x d(-1)) or sham-operated, and systolic blood pressures were measured at baseline and after 12 hours, 4 days, or 15 days. Blood pressure increased significantly after dexamethasone treatment. Isometric force generation was measured in endothelium-intact aortic ring segments. Aortas from dexamethasone-treated rats exhibited a significant time-dependent decrease in maximal relaxation to acetylcholine compared with control rats. Incubation with sepiapterin (10(-4) mol/L, 1 hour), which produces tetrahydrobiopterin via a salvage pathway, restored vasodilation to acetylcholine in aortas from 4- and 15-day dexamethasone-treated rats. GTP cyclohydrolase 1 mRNA expression levels also significantly decreased in a time-dependent manner. These results support the hypothesis that downregulation of GTP cyclohydrolase 1 contributes to increased blood pressure in glucocorticoid hypertensive rats.
authors.affiliation: Department of Physiology, CL-3162, Medical College of Georgia, Augusta, GA 30912, USA. brettmitchell@hotmail.com
authors.forename: Brett M
authors.initials: BM
authors.lastname: Mitchell
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dorrance
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000503:physiopathology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D007700:Kinetics; D008297:Male; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D012333:RNA, Messenger; D003907:Dexamethasone; D006136:GTP Cyclohydrolase