| Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide. | |
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MedLine Citation:
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PMID: 11425780 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined. METHODS AND RESULTS: lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids. CONCLUSIONS: Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity. |
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Authors:
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F Ruschitzka; T Quaschning; G Noll; A deGottardi; M F Rossier; F Enseleit; D Hürlimann; T F Lüscher; S G Shaw |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Circulation Volume: 103 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2001 Jun |
Date Detail:
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Created Date: 2001-06-26 Completed Date: 2001-08-09 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 3129-35 Citation Subset: AIM; IM |
Affiliation:
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Cardiology, Cardiovascular Research and Institute of Physiology, University Hospital Zürich, Zürich, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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11-beta-Hydroxysteroid Dehydrogenases Acetylcholine / pharmacology Animals Blood Pressure / drug effects Body Weight / drug effects Cells, Cultured Corticosterone / pharmacology Dose-Response Relationship, Drug Endothelin-1 / drug effects, metabolism, pharmacology Endothelins / genetics Endothelium, Vascular / cytology, drug effects, physiology Gene Expression Regulation / drug effects Glycyrrhizic Acid / pharmacology Heart Rate / drug effects Humans Hydroxysteroid Dehydrogenases / antagonists & inhibitors*, metabolism Hypertension / chemically induced, prevention & control* Male Nitrates / metabolism Nitric Oxide / physiology Nitric Oxide Synthase / drug effects, metabolism Nitric Oxide Synthase Type III Norepinephrine / pharmacology Phenylpropionates / pharmacology Potassium Chloride / pharmacology Protein Precursors / genetics Pyrimidines / pharmacology RNA, Messenger / drug effects, genetics, metabolism Rats Rats, Inbred WKY Receptor, Endothelin A Receptor, Endothelin B Receptors, Endothelin / antagonists & inhibitors*, genetics Vascular Diseases / physiopathology, prevention & control* Vasoconstriction / drug effects Vasodilation / drug effects Vasodilator Agents / pharmacology Verapamil / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Endothelin-1; 0/Endothelins; 0/LU 135252; 0/Nitrates; 0/Phenylpropionates; 0/Protein Precursors; 0/Pyrimidines; 0/RNA, Messenger; 0/Receptor, Endothelin A; 0/Receptor, Endothelin B; 0/Receptors, Endothelin; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 1405-86-3/Glycyrrhizic Acid; 50-22-6/Corticosterone; 51-41-2/Norepinephrine; 51-84-3/Acetylcholine; 52-53-9/Verapamil; 7447-40-7/Potassium Chloride; EC 1.1.-/Hydroxysteroid Dehydrogenases; EC 1.1.1.146/11-beta-Hydroxysteroid Dehydrogenases; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, rat |
| Comments/Corrections | |
Erratum In:
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Circulation 2001 Sep 4;104(10):1208 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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