Abstract-Loss-of-function mutations or inhibition of 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD-2) results in overstimulation of the mineralocorticoid receptor by cortisol and causes salt-sensitive hypertension. Traditionally, 11␤-HSD-2 activity has been assessed by measurement of the urinary cortisol metabolite ratio (tetrahydrocortisol [THF]ϩ5␣-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 (THFϩ5␣-THF)/THE and UFF/UFE ratios were 11Ϯ9% and 25Ϯ14% (PϽ0.001).(THFϩ5␣-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 (THFϩ5␣-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects. Absolute glycyrrhetinic acid-related increase in (THFϩ5␣-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 (THFϩ5␣-THF)/THE is lower than that of UFF/UFE. The UFF/UFE ratio does not appear to be more sensitive than (THFϩ5␣-THF)/THE for detection of decreased 11␤-HSD-2 activity. The (THFϩ5␣-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 11␤-HSD-2 in salt sensitivity.

Abstract. Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11␤HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THFϩ5␣THF)/THE as a parameter of 11␤HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THFϩ5␣THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 Ϯ 10/7 versus 115/73 Ϯ 8/6 mmHg; P Ͻ 0.001 for systolic; P Ͻ 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 Ϯ 0.05 to 1.18 Ϯ 0.04 mmol/L (P Ͻ 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 Ϯ 3.6 to 31.9 Ϯ 3.1 mol/L GFR (P Ͻ 0.01). Fractional calcium excretion increased from 2.4 Ϯ 0.3 to 2.7 Ϯ 0.3% (P Ͻ 0.01) and was negatively correlated to the fractional sodium excretion during GA (R ϭ Ϫ0.35; P Ͻ 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R ϭ 0.66; P Ͻ 0.0001). Inhibition of 11␤HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.