Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice‐induced hypertension

Background. The enzyme 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11‐dehydro derivatives. Inhibition of 11β‐HSD2 by liquorice‐derived glycyrrhizic acid (GA) therefore re...

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Published in:	Nephrology, dialysis, transplantation Vol. 16; no. 11; pp. 2146 - 2151
Main Authors:	Quaschning, Thomas, Ruschitzka, Frank, Niggli, Bernhard, Lunt, Carolyn M. B., Shaw, Sidney, Christ, Michael, Wehling, Martin, Lüscher, Thomas F.
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 01-11-2001
Subjects:	Animals Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Blood Vessels - drug effects Blood Vessels - physiopathology Cardiology. Vascular system Endothelin Receptor Antagonists endothelin‐1 endothelium Endothelium, Vascular - physiopathology Experimental diseases Glycyrrhiza - adverse effects glycyrrhizic acid Glycyrrhizic Acid - pharmacology Hypertension - etiology Hypertension - physiopathology liquorice Male Medical sciences Mineralocorticoid Receptor Antagonists nitric oxide Norepinephrine - pharmacology Potassium Chloride - pharmacology Rats Rats, Inbred WKY Renal Artery - drug effects Renal Circulation - drug effects Spironolactone - pharmacology Vasoconstriction - drug effects Vasoconstrictor Agents - pharmacology Vasodilation - drug effects Hypertension Endothelin Renal function Rat Steroid hormone Mineralocorticoid Peptide hormone Rodentia Cardiovascular disease Aldosterone Vertebrata Mammalia Animal Adrenal hormone Vasoconstrictor agent Antagonist Comparative study Biological receptor
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Summary:	Background. The enzyme 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11‐dehydro derivatives. Inhibition of 11β‐HSD2 by liquorice‐derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ETA receptor antagonist darusentan on renovascular endothelial function in liquorice‐induced hypertension. Methods. GA, a recognized inhibitor of 11β‐HSD2 was supplemented to the drinking water (3 g/l) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21, spironolactone (5.8±0.6 mg/kg/day), darusentan (45.2±6.5 mg/kg/day), or placebo was added to chow (n=7 per group). After the animals were killed, vascular function of isolated renal artery segments was assessed by isometric tension recording. Results. Relaxation of pre‐constricted renal artery segments in response to acetylcholine (10−10 to 10−5 mol/l) was impaired by GA as compared with controls (12±4% vs 98±5% of norepinephrine 3×10−7 mol/l), whereas endothelium independent relaxations were unaffected. Endothelin receptor antagonism improved renovascular endothelium‐dependent relaxation (32±4%, P<0.05 vs placebo) whereas endothelium‐dependent relaxation was completely normalized by aldosterone receptor antagonism (85±4%, P<0.01 vs placebo). Conclusions. In GA‐induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11β‐HSD2 activity.
Bibliography:	ark:/67375/HXZ-TF8L46B9-9 PII:1460-2385 istex:EB34962871D3A30D4DBD236357EA07101885AC1F local:162146 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0931-0509 1460-2385
DOI:	10.1093/ndt/16.11.2146