Impaired 11-beta hydroxysteroid dehydrogenase type 2 activity in sweat gland ducts in human essential hypertension.
The enzyme 11-beta hydroxysteroid dehydrogenase type 2 plays a major role in blood pressure regulation. It metabolizes glucocorticoid hormones into derivatives with low affinity for the mineralocorticoid receptor, preventing its permanent occupancy by circulating cortisol, which is 100- to 1000-fold more abundant than aldosterone in the plasma. Inactivating mutations of the enzyme result in severe hypertension, as seen in children with apparent mineralocorticoid excess syndrome. In patients with essential hypertension, however, attempts to evidence enzyme deficiency have been inconclusive. In this pilot study, its catalytic activity was measured directly in aldosterone-sensitive sweat gland ducts collected from skin biopsy samples of 10 male normotensive subjects and 10 subjects with essential hypertension (more than 140 to 90 mm Hg) with no sign of hypermineralocorticism. Isolated ducts were assayed for nicotinamide-dinucleotide-dependent dehydrogenase activity (transformation of tritiated corticosterone into tritiated-11 dehydrocorticosterone, as measured by high-pressure liquid chromatography). Hypertensive patients exhibited significantly lower 11-beta hydroxysteroid dehydrogenase type 2 activity (9.7+/-4.7 femtomoles per 3 mm length of duct and per 10 minutes incubation, median+/-SD) than did normotensive subjects (15.9+/-2.6). Such defect was undetectable using the classical urinary corticosteroid metabolism indexes, probably because of compensatory mechanisms. Relations between these findings and blood pressure levels should benefit from direct enzyme measurements in the vasculature. In conclusion, this cross-sectional study points to partial 11-beta hydroxysteroid dehydrogenase type 2 deficiency as a novel feature of essential hypertension, which should stimulate search for new signaling pathways and therapeutical targets.
Bocchi
Brigitte
B
INSERM U478, Faculté de Médecine X, Bichat, Université Paris 7, Paris, France.
Kenouch
Sabine
S
Lamarre-Cliche
Maxime
M
Muffat-Joly
Martine
M
Capron
Michel Hubert
MH
Fiet
Jean
J
Morineau
Gilles
G
Azizi
Michel
M
Bonvalet
Jean Pierre
JP
Farman
Nicolette
N
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000097:blood / Q000652:urine; D000328:Adult; D000450:Aldosterone / Q000097:blood; D001639:Bicarbonates / Q000097:blood; D001706:Biopsy; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid; D003345:Corticosterone / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D004573:Electrolytes / Q000097:blood / Q000652:urine; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000652:urine; D008297:Male; D008875:Middle Aged; D009243:NAD / Q000378:metabolism; D010865:Pilot Projects; D012083:Renin / Q000097:blood; D012680:Sensitivity and Specificity; D013545:Sweat Glands / Q000201:enzymology*; D014527:Uric Acid / Q000097:blood
D000305:Adrenal Cortex Hormones; D001639:Bicarbonates; D001786:Blood Glucose; D004573:Electrolytes; D009243:NAD; D014527:Uric Acid; D000450:Aldosterone; D003404:Creatinine; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D012083:Renin; D003345:Corticosterone