GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats

Brett M. Mitchell, Anne M. Dorrance, R. Clinton Webb

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 · 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.

Original languageEnglish (US)
Pages (from-to)669-674
Number of pages6
JournalHypertension
Volume41
Issue number3 II
DOIs
StatePublished - Mar 1 2003

Fingerprint

Guanosine Triphosphate
Glucocorticoids
Down-Regulation
Hypertension
Dexamethasone
Blood Pressure
Vasodilation
Acetylcholine
Aorta
Vasodilator Agents
Nitric Oxide Synthase
Endothelium
Maintenance
sapropterin
Messenger RNA
Enzymes

Keywords

  • Endothelial nitric oxide synthase
  • Endothelium
  • Glucocorticoids
  • Hypertension, experimental

ASJC Scopus subject areas

  • Internal Medicine

Cite this

GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats. / Mitchell, Brett M.; Dorrance, Anne M.; Webb, R. Clinton.

In: Hypertension, Vol. 41, No. 3 II, 01.03.2003, p. 669-674.

Research output: Contribution to journalArticle

Mitchell, Brett M. ; Dorrance, Anne M. ; Webb, R. Clinton. / GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats. In: Hypertension. 2003 ; Vol. 41, No. 3 II. pp. 669-674.
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