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Background —The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11β-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11β-HSD in the regulation of vascular tone remains to be determined.Methods and Results —Glycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11β-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls;P &lt;0.01). After 11β-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (allP &lt;0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P &lt;0.05 versus controls). Chronic ETA receptor blockade with LU135252 (50 mg · kg−1 · d−1 ) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P &lt;0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11β-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids.Conclusions —Chronic ETA receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11β-HSD inhibitor–induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11β-HSD activity.

Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11β-Hydroxysteroid Dehydrogenase Inhibition