Tetrahydrobiopterin-Dependent Vasodilation is Impaired in Experimental Hypertension

Hdl Handle:
http://hdl.handle.net/10675.2/552365
Title:
Tetrahydrobiopterin-Dependent Vasodilation is Impaired in Experimental Hypertension
Authors:
Mitchell, Brett M.
Abstract:
Decreased nitric oxide (NO) bioavailability leads to decreased vasodilation and increased blood presssure. Adequate amounts of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH4), optimizes NO production. Reduced BH4 results in decreased NO and increased superoxide production. Therefore, we hypothesized that decreased GTP cyclohydrolase (GTPCH), the rate-limiting enzyme in BH4 production, decreases NO leading to impaired vasodilation and increased blood pressure. To examine the effect of in vivo GTPCH inhibition on vasodilation and blood pressure, we administered DAHP in the drinking water of rats. Systolic blood pressure increased significantly in DAHP-treated rats. Endothelium-dependent relaxation was decreased in aortas from DAHP-treated rats, but restored with superoxide dismutase or sepiapterin, which produces BH4 via a salvage pathway. In conclusion, in vivo GTPCH inhibition leads to decreased NO production resulting in decreased BH4-dependent vasodilation and increased blood pressure. Excess glucocorticoids (GC) cause hypertension. To assess the effect of GCs on BH4 biosynthesis and vasodilation, we implanted dexamethasone (DEX), a synthetic GC, in rats. Aortas were isolated after 12 hours, 4 days, or 15 days of DEX-treatment to examine the role of GTPCH in the onset, development, and maintenance of GC-induced hypertension, respectively. Aortic relaxation and GTPCH and eNOS mRNA levels were decreased significantly in aortas from 4- and 15-day DEX-treated rats and restored with sepiapterin. In conclusion, excess GCs down-regulate GTPCH leading to decreased BH4-dependent vasodilation, which contributes to GC-induced hypertension. To assess if GCs act directly on the blood vessel to down-regulate GTPCH and decrease vasodilation, we incubated rat aortic rings with various compounds and found endothelium-dependent relaxation and GTPCH mRNA decreased significantly following incubation with DEX for 6 hours. This effect was blocked by a GC receptor antagonist and reversed by sepiapterin. In conclusion, GCs act through the GC receptor to down-regulate GTPCH leading to decreased BH4- dependent vasodilation. The results support the overall hypothesis that decreased BH4 biosynthesis, either by GCs or pharmacological inhibition, results in decreased NO production leading to reduced vasodilation and increased blood pressure.
Affiliation:
Department of Physiology
Issue Date:
May-2003
URI:
http://hdl.handle.net/10675.2/552365
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/305295955?accountid=12365
Type:
Dissertation
Appears in Collections:
Department of Physiology Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorMitchell, Brett M.en
dc.date.accessioned2015-05-07T02:50:13Zen
dc.date.available2015-05-07T02:50:13Zen
dc.date.issued2003-05en
dc.identifier.urihttp://hdl.handle.net/10675.2/552365-
dc.description.abstractDecreased nitric oxide (NO) bioavailability leads to decreased vasodilation and increased blood presssure. Adequate amounts of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH4), optimizes NO production. Reduced BH4 results in decreased NO and increased superoxide production. Therefore, we hypothesized that decreased GTP cyclohydrolase (GTPCH), the rate-limiting enzyme in BH4 production, decreases NO leading to impaired vasodilation and increased blood pressure. To examine the effect of in vivo GTPCH inhibition on vasodilation and blood pressure, we administered DAHP in the drinking water of rats. Systolic blood pressure increased significantly in DAHP-treated rats. Endothelium-dependent relaxation was decreased in aortas from DAHP-treated rats, but restored with superoxide dismutase or sepiapterin, which produces BH4 via a salvage pathway. In conclusion, in vivo GTPCH inhibition leads to decreased NO production resulting in decreased BH4-dependent vasodilation and increased blood pressure. Excess glucocorticoids (GC) cause hypertension. To assess the effect of GCs on BH4 biosynthesis and vasodilation, we implanted dexamethasone (DEX), a synthetic GC, in rats. Aortas were isolated after 12 hours, 4 days, or 15 days of DEX-treatment to examine the role of GTPCH in the onset, development, and maintenance of GC-induced hypertension, respectively. Aortic relaxation and GTPCH and eNOS mRNA levels were decreased significantly in aortas from 4- and 15-day DEX-treated rats and restored with sepiapterin. In conclusion, excess GCs down-regulate GTPCH leading to decreased BH4-dependent vasodilation, which contributes to GC-induced hypertension. To assess if GCs act directly on the blood vessel to down-regulate GTPCH and decrease vasodilation, we incubated rat aortic rings with various compounds and found endothelium-dependent relaxation and GTPCH mRNA decreased significantly following incubation with DEX for 6 hours. This effect was blocked by a GC receptor antagonist and reversed by sepiapterin. In conclusion, GCs act through the GC receptor to down-regulate GTPCH leading to decreased BH4- dependent vasodilation. The results support the overall hypothesis that decreased BH4 biosynthesis, either by GCs or pharmacological inhibition, results in decreased NO production leading to reduced vasodilation and increased blood pressure.en
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/305295955?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjecttetrahydrobiopterinen
dc.subjectNitric Oxideen
dc.subjectGlucocorticoiden
dc.subjectHypertensionen
dc.titleTetrahydrobiopterin-Dependent Vasodilation is Impaired in Experimental Hypertensionen
dc.typeDissertationen
dc.contributor.departmentDepartment of Physiologyen
dc.description.advisorWebb, R. C.en
dc.description.committeeBergeron; Brands; Inscho; Pollocken
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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