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: Brett M Mitchell, Anne M Dorrance, R Clinton Webb
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 41 Issue 3 Pt 2 Pg. 669-74 (Mar 2003) ISSN: 1524-4563 [Electronic] United States
• PMID: 12623977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Glucocorticoids
• RNA, Messenger
• Dexamethasone
• GTP Cyclohydrolase

Topics

• Animals
• Aorta (drug effects, physiopathology)
• Blood Pressure
• Dexamethasone (pharmacology)
• Down-Regulation
• Endothelium, Vascular (physiopathology)
• GTP Cyclohydrolase (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Glucocorticoids (pharmacology)
• Hypertension (chemically induced, enzymology, physiopathology)
• Kinetics
• Male
• Organ Culture Techniques
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Vasodilation (drug effects)