(Hypertension. 2001;37:801.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Aldosterone Receptor Antagonism Normalizes Vascular Function in Liquorice-Induced Hypertension
From the Institute of Physiology (T.Q.), Cardiovascular Research, University of Zürich, Zürich; the Cardiovascular Center (F.R., T.F.L.), Cardiology, University Hospital Zürich, Zürich; and the Department of Clinical Research (S.S.), Inselspital, University of Bern, Bern, Switzerland.
Correspondence to Thomas F. Lüscher, MD, FRCP, FACC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail cardiotfl{at}GMX.CH
The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (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 days 8 to 21, spironolactone (5.8±0.6 mg · kg-1 · d-1), eplerenone (182±13 mg · kg-1 · d-1), or placebo was added to the chow (n=7 animals per group). Endothelium-dependent or -independent vascular function was assessed as the relaxation of preconstricted aortic rings to acetylcholine or sodium nitroprusside, respectively. In addition, aortic endothelial nitric oxide synthase (eNOS) protein content, nitrate tissue levels, and endothelin-1 (ET-1) protein levels were determined. GA increased systolic blood pressure from 142±8 to 185±9 mm Hg (P<0.01). In the GA group, endothelium-dependent relaxation was impaired compared with that in controls (73±6% versus 99±5%), whereas endothelium-independent relaxation remained unchanged. In the aortas of 11ß-HSD2–deficient rats, eNOS protein content and nitrate tissue levels decreased (1114±128 versus 518±77 µg/g protein, P<0.05). In contrast, aortic ET-1 protein levels were enhanced by GA (308±38 versus 497±47 pg/mg tissue, P<0.05). Both spironolactone and eplerenone normalized blood pressure in animals on GA (142±9 and 143±9 mm Hg, respectively, versus 189±8 mm Hg in the placebo group; P<0.01), restored endothelium-dependent relaxation (96±3% and 97±3%, respectively, P<0.01 versus placebo), blunted the decrease in vascular eNOS protein content and nitrate tissue levels, and normalized vascular ET-1 levels. This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11ß-HSD2–deficient hypertension.
Key Words: 11ß-hydroxysteroid dehydrogenase • endothelin-1, endothelium • glycyrrhizic acid • nitric oxide
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