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(Hypertension. 2003;41:669.)
© 2003 American Heart Association, Inc.

Scientific Contributions

GTP Cyclohydrolase 1 Downregulation Contributes to Glucocorticoid Hypertension in Rats

From the Department of Physiology, Medical College of Georgia, Augusta.

Correspondence to Brett M. Mitchell, MS, Department of Physiology, CL-3162, Medical College of Georgia, Augusta, GA 30912. E-mail brettmitchell{at}hotmail.com

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 · kg^-1 · 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.

Key Words: glucocorticoids • endothelial nitric oxide synthase • endothelium • hypertension, experimental

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