(Circulation. 2001;103:3129.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11ß-Hydroxysteroid Dehydrogenase Inhibition
Role of Nitric Oxide
From Cardiology (F.R., T.Q., G.N., F.E., D.H., T.F.L.), Cardiovascular Research and Institute of Physiology, University Hospital Zürich, Zürich, Switzerland; Department of Endocrinology and Diabetology (A.dG., M.R.), University Hospital Geneva, Geneva, Switzerland; and Department of Clinical Research (S.G.S.), University Hospital Bern, Bern, Switzerland.
Correspondence to Sidney Shaw, PhD, Department of Clinical Research, University Hospital Bern, Inselsprhal, 3010 Bern, Switzerland. E-mail sidney.shaw{at}dkf5.unibe.ch
Background—The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11ß-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11ß-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 11ß-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11ß-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 11ß-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 11ß-HSD inhibitor–induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11ß-HSD activity.
Key Words: endothelin • nitric oxide • hypertension
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