The role of 11β-hydroxysteroid dehydrogenase in the pathogenesis of hypertension

The two 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) isozymes catalyze the interconversion of cortisol and cortisone. Type 1 11 beta-HSD (11 beta-HSD1) has bidirectional activity, while type 2 11 beta-HSD (11 beta-HSD2) mainly converts cortisol into cortisone. Of these two hormones only cortisol has affinity to mineralocorticoid receptors (MRs) and thus induces mineralocorticoid effects. A normal activity of 11 beta-HSD2 is crucial for prevention of mineralocorticoid activity of cortisol. Absent or decreased 11 beta-HSD2 activity results in cortisol-mediated hypermineralocorticoid hypertension. In several hypertensive syndromes a decreased 11 beta-HSD2 activity has been described as the pathogenetic mechanism of the increased blood pressure. In the apparent mineralocorticoid excess (AME) syndrome type 1, absence of 11 beta-HSD, activity is caused by mutations in the gene coding for 11 beta-HSD2, In licorice-induced hypertension glycyrrhetinic acid, the active substituent of licorice, inhibits 11 beta-HSD2 resulting in an acquired hypermineralocorticoid state. 11 beta-HSD2 activity is not decreased in glucocorticoid hypertension (Cushing's syndrome). In essential hypertension some evidence for decreased systemic and skin activity of 11 beta-HSD1 and/or 11 beta-HSD2 has been found, while renal activity of both isozymes appears to be normal. 11 beta-HSD2 activity is also present in cardiovascular myocytes of humans and dogs, and inhibition of 11 beta-HSD potentiates the vascular response to catecholamines. Although MRs in the central nervous system have been incriminated in the pathogenesis of mineralocorticoid hypertension, a pathophysiological role for 11 beta-HSD2 has not yet been described. Finally, in the placenta 11 beta-HSD2 reduces fetal exposure to maternal glucocorticoids and a decreased activity of this isozyme may result in low birth weight and increased risk of high blood pressure at adult age. (C) 1998 Elsevier Science B.V.