Nephrol Dial Transplant (2001) 16: 2146-2151
© 2001 European Renal Association-European Dialysis and Transplant Association
Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice-induced hypertension
1 Institute of Physiology, Cardiovascular Research, University of Zürich, 2 Cardiovascular Center, Cardiology, University of Zürich, Switzerland, 3 Department of Clinical Research, Inselspital, University of Bern, Switzerland and 4 Institute of Clinical Pharmacology, University of Mannheim, Germany
Background. The enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11ß-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 11ß-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 3x10-7 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 11ß-HSD2 activity.
Keywords: endothelin-1; endothelium; glycyrrhizic acid; liquorice; nitric oxide
* Both authors contributed equally to this work.
Correspondence and offprint requests to: Thomas F. Lüscher, MD, FRCP, FACC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. Email: cardiotfl{at}gmx.ch
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