The role of 11 beta-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 mineral corticoid excess (AME) syndrome type 1, absence of 11 beta-HSD2 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.
van Uum
S H
SH
Department of Medicine, St. Radboud University Hospital, University of Nijmegen, Netherlands. s.vanuum@aig.azn.nl
Hermus
A R
AR
Smits
P
P
Thien
T
T
Lenders
J W
JW
D042842:11-beta-Hydroxysteroid Dehydrogenases; D003348:Cortisone / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000502:physiology*; D006973:Hypertension / Q000201:enzymology*; D007527:Isoenzymes / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
D007527:Isoenzymes; D018161:Receptors, Mineralocorticoid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone