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


Quaschning, Thomas; Ruschitzka, Frank; Niggli, Bernhard; Lunt, Carolyn M B; Shaw, Sidney; Christ, Michael; Wehling, Martin; Lüscher, Thomas F (2001). Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice‐induced hypertension. Nephrology, Dialysis, Transplantation, 16(11):2146-2151.

Abstract

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

Abstract

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

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Nephrology
Health Sciences > Transplantation
Language:English
Date:1 November 2001
Deposited On:25 Sep 2018 14:25
Last Modified:15 Apr 2020 21:11
Publisher:Oxford University Press
ISSN:0931-0509
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/ndt/16.11.2146
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101093ndt16112146 (Library Catalogue)

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