The
enzyme 11beta-hydroxysteroid dehydrogenase (11beta-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
11beta-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 11beta-HSD2-deficient rats, eNOS
protein content and
nitrate tissue levels decreased (1114+/-128 versus 518+/-77 microgram/
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 11beta-HSD2-deficient
hypertension.