Urinary free cortisol is not a biochemical marker of hypertension

Background: Increasing evidence suggests that glucocorticoids might play a role in blood pressure (BP) control. These reports show that cortisol (F) can increase the BP acting on the mineralocorticoid receptor in kidney, brain, heart, and blood vessel. The aim of this study was to evaluate the effects of F in the renal salt and water reabsorption in essential hypertensive patients (EH). Methods: We studied 364 EH and 102 normotensive (NT) subjects. We obtained 24-h urine to measure urinary free cortisol (UFF) and creatinine (Cr). The upper limit of the UFF/Cr ratio was calculated from NT subjects. Patients with a high UFF/Cr ratio underwent dexamethasone suppression test (DST). Blood samples were used to determine plasma renin activity (PRA), aldosterone (SA), F, cortisone (E), urinary Na/K ratios, adrenocorticotrophic hormone levels, and also to purify lymphocytes for binding assays and genetic analysis. Results: In EH subjects the UFF/Cr and F/E ratios were higher than in normotensives (48.3 mu g/g [33.6 to 57.5 mu g/g] v 32.6 mu g/g [5.6 to 34.6 mu g/g], P<.001 and 3.9 mu g/g [3.3 to 4.8 mu g/g] v 3.0 mu g/g [2.4 to 3.6 mu g/g], respectively), whereas the SA and PRA levels were similar. The upper limit value for UFF/Cr was set at 51.6 mu g/g. The EH patients with high UFF/Cr (123/364, 34%) had lower PRA (1.5 ng/mL/h [0.9 to 2.5 ng/mL/h] v 2.0 ng/mL/h [1.1 to 3.0 ng/mL/h], P=.012, SA levels (7.1 ng/dL [4.1 to 10.5 ng/dL] v 7.9 ng/dL [5.2 to 11.0 ng/dL], P=.045) and Na/K ratios (3.6 [2.8 to 5.8] v 4.0 [3.1 to 6.6], P <=.05) than those with normal UFF/Cr ratios. We found a slight negative relationship between UFF/Cr and PRA (r = -0.117, P=.031), SA (r = -0.096, P=.058) and Na/K ratios (r = 0.176, P =.059). We did not find significant differences in serum F/E ratios between EH patients with high or normal UFF/Cr (3.9 [3.3 to 5.1] v 3.8 [3.2 to 4.7], P = not significant [NS]) or a correlation between F/E ratio and UFF excretion (r = 0.032, P = NS). We did not find any association between UFF/Cr with systolic BP (P=.349) or diastolic BP (P=.895). Forty EH with the highest UFF/Cr values underwent the DST, which resulted in suppressed serum F in all of them. Binding assays in 4 of 13 EH with the highest UFF/Cr ratio showed a low affinity to dexamethasone (K-d 13.7 to 33.0 nmol/L). The polymerase chain reaction (PCR) amplification of the GR gene (ligand-binding domain exons) did not show mutations or gross alterations. Conclusions: We found an EH subpopulation with abnormally high values of UFF but evidence of only a minor mineralocorticoid action, which was not directly related to the BP elevation, suggesting that another alternative mechanism could be triggering the F-induced hypertension. The origin of hypercortisoluria was not elucidated; however, a subtle glucocorticoid resistance was found in some cases.