Aldosterone Receptor Antagonism Normalizes Vascular Function in 11β-Hydroxysteroid Dehydrogenase Deficient Hypertension
Background: The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolising glucocorticoids to their receptor inactive 11-dehydro derivatives. The present study investigated the effect of the aldosterone receptor antagonist spironolactone on endothelial function in liquorrhice induced hypertension. Methods: Glycyrrhizic acid (GA), a recognised inhibitor of 11β-HSD2 was supplemented to the drinking water (3g/L) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21 spirolonoactone (5.8±0.6 mg/kg/d) or placebo was added to chow (n=7/group). Endothelium-dependent and -independent vascular function was assessed as relaxation of preconstricted aortic rings to acetylcholine (10-10-10-5 mol/L) or sodium nitroprusside (10-10-10-5 mol/L). Furthermore aortic eNOS protein content, nitrate tissue levels, endothelin-1 (ET-1) protein levels were determined. Results: GA application increased SBP to 185±9 mmHg vs 142±8 mmHg in control animals, p<0.01). In the GA group endothelium-dependent relaxation was impaired as compared to controls (73±6% vs 99±5% of norepinephrine 3x10-7 mol/L), whereas endothelium independent relaxation remained unchanged. In the aorta of 11β-HSD2 deficient rats, eNOS protein content and nitrate tissue levels (1114±128 vs 518±77μg/g protein, p<0.05) decreased. In contrast, aortic endothelin-1 (ET-1) protein levels were enhanced by GA. (308±38 vs 497±47 pg/mg tissue, p<0.05). Treatment with spironolactone normalized blood pressure in animals on GA (142±9 mmHg vs 189±8 mmHg in the placebo group; p<0.01) and restored endothelium-dependent relaxation (96±3%, p<0.01 vs placebo). Spironolactone furthermore blunted the decrease in vascular eNOS protein content and nitrate tissue levels as well as the elevation of ET-1 protein levels. Conclusion: In 11β-HSD2-deficient hypertension, aldosterone receptor antagonism normalizes blood pressure, prevents up-regulation of vascular ET-1 and restores NO-mediated endothelial dysfunction and therefore may advance as a novel therapeutic approach.