In vivo 11beta-HSD-2 activity: variability, salt-sensitivity, and effect of licorice.
Loss-of-function mutations or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) results in overstimulation of the mineralocorticoid receptor by cortisol and causes salt-sensitive hypertension. Traditionally, 11beta-HSD-2 activity has been assessed by measurement of the urinary cortisol metabolite ratio (tetrahydrocortisol [THF]+5alpha-THF)/tetrahydrocortisone (THE). Recently, the ratio of urinary free glucocorticoids, UFF/UFE, has been suggested to be a more reliable parameter, an aspect that has not been investigated systematically. Steroid metabolites were measured repeatedly by gas chromatography-mass spectrometry in 20 healthy subjects at baseline and after 1 week each of a 30- or 180-mmol/d of sodium diet or 500 mg/d of glycyrrhetinic acid. Intraindividual coefficients of variation from 3 random urine collections for (THF+5alpha-THF)/THE and UFF/UFE ratios were 11+/-9% and 25+/-14% (P<0.001). (THF+5alpha-THF)/THE was more sensitive than UFF/UFE for detection of glycyrrhetinic acid-induced increases higher than the upper 95% confidence interval of the coefficient of variation of the corresponding ratio. Low- or high-salt diet did not alter either ratio. Mean (THF+5alpha-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects. Absolute glycyrrhetinic acid-related increase in (THF+5alpha-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects and correlated with changes in mean BP. Intraindividual variability of (THF+5alpha-THF)/THE is lower than that of UFF/UFE. The UFF/UFE ratio does not appear to be more sensitive than (THF+5alpha-THF)/THE for detection of decreased 11beta-HSD-2 activity. The (THF+5alpha-THF)/THE ratio better discriminates between salt-sensitive and salt-resistant subjects. Together with BP responses to glycyrrhetinic acid, these findings support a pivotal role of 11beta-HSD-2 in salt sensitivity.
Ferrari
P
P
Division of Nephrology and Hypertension, Inselspital, University of Berne, Switzerland. paolo.ferrari@insel.ch
Sansonnens
A
A
Dick
B
B
Frey
F J
FJ
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004573:Electrolytes / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006034:Glycyrrhetinic Acid / Q000097:blood / Q000494:pharmacology*; D006035:Glycyrrhiza; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000652:urine*; D008297:Male; D011446:Prospective Studies; D012982:Sodium, Dietary / Q000008:administration & dosage*; D013760:Tetrahydrocortisol / Q000652:urine; D013761:Tetrahydrocortisone / Q000652:urine
D004573:Electrolytes; D012982:Sodium, Dietary; D013761:Tetrahydrocortisone; D013760:Tetrahydrocortisol; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D006034:Glycyrrhetinic Acid