GTP Cyclohydrolase 1 Downregulation Contributes to Glucocorticoid Hypertension in Rats

Abstract

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...

The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis

“…Both cyclic adenosine monophosphatedependent protein kinase and stress-activated protein kinases are able to activate GTP cyclohydrolase gene transcription in normal conditions. 37 By contrast, glucocorticoids decrease GTPCH gene transcription, 38,39 and transforming growth factor beta (TGF-␤) has been shown to counterbalance the cytokine activation of nitric oxide synthase in endothelial cells by down-regulating GTPCH mRNA expression. [40][41][42] Because increased levels of TGF-␤ are present in cirrhosis, speculating that TGF-␤ could play a role in the decreased GTPCH expression found in cirrhosis is tempting.…”

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

“…First, the increased levels of vascular superoxide anions in hypertension might directly inactivate NO. 35,36 Second, the improvement of endothelium-dependent NO-mediated response by the addition of synthetic tetrahydrobiopterin, or its intermediate donor sepiapterin, to vessel rings from animals with hypertension 3,4 suggests that diminished levels of this eNOS cofactor may contribute to the endothelial dysfunction related to NO deficiency. Third, the downregulation of eNOS expression in the coronary arterioles from hypertensive animals, as revealed by immunohistochemistry herein, is another potential mechanism.…”

“…For example, there is a markedly reduced endothelium-dependent vasodilation in both large and small coronary arteries from hypertensive humans and animal models of hypertension. 1 Mounting evidence suggests that this vascular impairment may be related to a diminished production and bioavailability of the potent vasodilator nitric oxide (NO), which may result from an increased vascular production of superoxide anion 2 or decreased endothelial levels of tetrahydrobiopterin 3,4 or L-arginine. 5 Interestingly, administration of NO precursor L-arginine restores endothelium-mediated vasodilatory function in patients with essential hypertension, 5 improves coronary hemodynamics in spontaneously hypertensive rats, 6 and increases NO production and reduces blood pressure in hypertensive rats with 7 or without 8 renal failure.…”

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

“…27,28 In a glucocorticoid-induced rat model of hypertension, GTPCH mRNA levels were reduced, and impaired endotheliumdependent relaxations could be restored by incubating vessels in sepiapterin, which suggests reduced BH4 bioavailability as a cause of eNOS uncoupling. 89 However, it was not determined whether these abnormalities were a direct effect of glucocorticoid treatment or secondary to the experimental hypertension, and the relevance of these findings to human vascular disease remains uncertain. More recent studies in the DOCA-salt hypertensive mouse also found that decreased BH4 levels were related to reduced GTPCH activity; supplementation of BH4 or increased BH4 synthesis by adenoviral gene delivery of GTPCH restored BH4 levels and normalized eNOS function.…”