Mineralocorticoid receptor also modulates basal activity of hypothalamus-pituitary-adrenocortical system in humans

Hippocampal mineralocorticoid (MRs) and glucocorticoid receptors (GRs) have been demonstrated to regulate the activity of the hypothalamus-pituitary-adrenocortical (HPA) system. To elucidate the role of the hippocampal MR in the circadian activity of the human HPA system, we studied diurnal secretory profiles of corticotropin (ACTH) and cortisol in 10 healthy male humans before and after an 8-day treatment with the MR antagonist spironolactone. 24-hour blood sampling at 30-min intervals was performed for estimation of cortisol (q30) and ACTH (q120). Saliva cortisol was measured for estimation of unbound cortisol. At the end of the 24-hour sampling period a corticotropin-releasing hormone (CRH) challenge was performed. High plasma concentrations of the active metabolite canrenone were achieved (begin of sampling: 2,653 +/- 693 nmol/l; end of sampling: 747 +/- 177 nmol/l). There was a significant increase in the diurnal minima (37.1 +/- 13.3 vs. 23.7 +/- 8.9 nmol/l, p < 0.02) and mean cortisol (193.5 +/- 25.8 vs. 173.0 +/- 23. 0 nmol/l, p < 0.03) plasma concentrations. However, the diurnal peak concentrations and pulsatile secretory features were unchanged after spironolactone treatment. For saliva cortisol, the only significant treatment difference was a decrease in the diurnal amplitude of cortisol relative to the diurnal mean concentration (2.56 +/- 0.47 vs. 3.11 +/- 0.87, p < 0.03). After spironolactone treatment there was a decrease in diurnal mean ACTH concentrations (46.2 +/- 14.4 vs. 41.8 +/- 10.3 pmol/l). There was no difference in the ACTH and cortisol response after infusion of CRH before and after spironolactone treatment. CBG plasma concentrations were significantly increased (22.4 +/- 2.3 vs. 19.2 +/- 2.7 mg/l, p < 0. 01) after spironolactone treatment, which possibly contributed to the observed increase in plasma cortisol. In summary, as predicted from animal studies we found significant effects of MR antagonization to be restricted to time windows of low HPA system activity. These findings are similar to the effects of aging upon the HPA system. However, the effect of spironolactone treatment was small, suggesting that the HPA system activity in humans is modulated but not regulated by the hippocampal MR.