Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamus-pituitary-adrenal (HPA) axis in humans

Context: Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of the hypothalamus-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids, which maintains the basal HPA activity. The systemic administration of MR antagonists enhances spontaneous and CRH-stimulated ACTH, cortisol and dehydroepiandrosterone (DHEA) secretion, while the effects of chronic treatment with MR antagonists are scanty. Our study was performed in order to clarify this point. Design: ACTH, cortisol and DHEA levels were studied during placebo, canrenoate, a MR antagonist (CAN, 200 mg iv-bolus at 16.00h followed by 200 mg infused over 4h) and hCRH (2.0 μg/kg iv-bolus at 18.00h) before and during the last week of 28-day treatment with CAN (200 mg/day p.o.) in eight young women. Results: pre-treatment sessions: CAN and hCRH administration increased ACTH, cortisol and DHEA levels vs placebo (p<0.05). Post-treatment sessions: during placebo, cortisol and DHEA were significantly amplified vs pre-treatment session (p<0.05), while ACTH levels were not modified; CAN infusion, differently from pre-treatment session, was not able to significantly increase ACTH, cortisol and DHEA levels; ACTH, cortisol and DHEA responses to hCRH were amplified respect to pre-treatment session, although statistical significance was obtained for cortisol and DHEA only. Conclusions: MR blockade by acute CAN administration significantly enhances the HPA activity in the afternoon, during the quiescent phase of the circadian rhythm. At the same period, prolonged treatment with CAN amplifies both spontaneous and CRH-stimulated activity of the HPA axis while it blunts the HPA rensponsiveness to a further MR-mediated stimulation.