Endothelin 1 type A receptor antagonism prevents vascular dysfunction and hypertension induced by 11β-hydroxysteroid dehydrogenase inhibition: Role of nitric oxide

Abstract

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<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 (all P<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<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<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.