IMPAIRED CORTISOL BINDING TO GLUCOCORTICOID RECEPTORS IN HYPERTENSIVEPATIENTS

We compared glucocorticoid receptor binding characteristics and glucoc orticoid responsiveness of human mononuclear leukocytes (HML) from hyp ertensive patients and matched normotensive volunteers. We also consid ered associations of these variables with plasma renin activity, aldos terone, cortisol, corticotropin, and electrolyte concentrations. We ca lculated binding affinity (K-d; nmol/L) and capacity (B-max; sites/cel l) for dexamethasone and cortisol from homologous and heterologous com petition curves for specific [H-3]dexamethasone binding sites on HML i solated from the blood of normotensive volunteers and subjects with es sential hypertension. Glucocorticoid responsiveness of HML was evaluat ed as IC50 values (nmol/L) for dexamethasone and cortisol for the inhi bition of lysozyme release. We measured plasma hormones by radioimmuno assay. K-d values (mean+/-SE) for cortisol in HML of hypertensive pati ents were higher than in control subjects (24.6+/-24 versus 17.5+/-1.7 nmol/L, P<.04). Binding capacity (4978+/-391 versus 4131+/-321 sites/ cell), Kd values for dexamethasone (6.7+/-0.5 versus 5.7+/-0.3 nmoL/L) , and IC50 values for dexamethasone (3.4+/-0.3 versus 3.1+/-0.2 nmol/L ) and cortisol (12.2+/-1.6 versus 9.5+/-0.3 nmol/L) were not significa ntly different. Patients with renin values less than 0.13 ng angiotens in I/L per second were markedly less sensitive to cortisol than those with higher values. Both K-d (30.3+/-2.5 versus 19.2+/-2.4 nmol/L) and IC50 values (15.5+/-1.8 versus 8.9+/-1.2 nmol/L) for cortisol were si gnificantly higher in patients with lower renin values (P<.03). Other variables, including plasma hormone and electrolyte values and binding characteristics for dexamethasone, were not different. These data sug gest that cortisol binding to glucocorticoid receptor is slightly impa ired in patients with essential hypertension. In vivo, this could lead to inappropriate binding of cortisol to mineralocorticoid receptors. Hence, decreased sensitivity to cortisol is associated with renin supp ression. This hypothesis is supported by evidence of hypertension and low renin activity, which others have described in patients with prima ry glucocorticoid resistance due to mutations of the glucocorticoid re ceptor.