Document Detail

Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide.
MedLine Citation:
PMID:  11425780     Owner:  NLM     Status:  MEDLINE    
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.
F Ruschitzka; T Quaschning; G Noll; A deGottardi; M F Rossier; F Enseleit; D Hürlimann; T F Lüscher; S G Shaw
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  103     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-26     Completed Date:  2001-08-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3129-35     Citation Subset:  AIM; IM    
Cardiology, Cardiovascular Research and Institute of Physiology, University Hospital Zürich, Zürich, Switzerland.
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MeSH Terms
11-beta-Hydroxysteroid Dehydrogenases
Acetylcholine / pharmacology
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
Hydroxysteroid Dehydrogenases / antagonists & inhibitors*,  metabolism
Hypertension / chemically induced,  prevention & control*
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, 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
Reg. No./Substance:
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 Dehydrogenases; EC protein, human; EC Oxide Synthase; EC Oxide Synthase Type III; EC protein, rat
Erratum In:
Circulation 2001 Sep 4;104(10):1208

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