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The Antihypertensive Effects and Mechanisms of Huotan Jiedu Tongluo Decoction in Rats with H-Type Hypertension
Published on: May 17, 2024
GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats
Brett M Mitchell1, Anne M Dorrance, R Clinton Webb
1Department of Physiology, CL-3162, Medical College of Georgia, Augusta, GA 30912, USA. brettmitchell@hotmail.com
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.
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