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 ⅐ kg Ϫ1 ⅐ d Ϫ1 ) 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 dexamethasonetreated rats exhibited a significant time-dependent decrease in maximal relaxation to acetylcholine compared with control rats. Incubation with sepiapterin (10 Ϫ4 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. Key Words: glucocorticoids Ⅲ endothelial nitric oxide synthase Ⅲ endothelium Ⅲ hypertension, experimental G lucocorticoids are among the most widely prescribed drugs by physicians, and excess glucocorticoids can elevate blood pressure in humans (Cushing's syndrome) and animals. [1][2][3] Previous studies have shown that glucocorticoid hypertension is associated with an increased pressor response to angiotensin II and norepinephrine, and reduced production of vasodilators. 3,4 In addition, endothelium-dependent vasodilation has been shown to be reduced in blood vessels from humans and animals with glucocorticoid hypertension. 1,4,5 A reduction in the bioavailability of NO, a potent vasodilator, has been implicated in glucocorticoid-induced hypertension, and glucocorticoids affect many proteins involved in NOmediated vasodilation. 6 NO plays a key role in vascular tone, and decreases in NO production and bioavailability have been shown to reduce endothelium-dependent dilation and increase blood pressure. NO can be produced by the conversion of arginine and oxygen to citrulline via 3 isoforms of NO synthase (NOS). Endothelial NOS (eNOS) requires the cofactor tetrahydrobiopterin (BH4), which aids in the stabilization of the eNOS dimer and increases the affinity of eNOS for arginine. 7 BH4 is pro...