Effect of acute and prolonged mineralocorticoid receptor blockade on spontaneous and stimulated hypothalamic-pituitary-adrenal axis in humans.
BACKGROUND
Mineralocorticoid receptors (MRs) in the hippocampus display an important role in the control of the hypothalamic-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 DHEA secretion, while the effects of chronic treatment with MR antagonists are scanty. Our study was performed in order to clarify this point.


METHODS
ACTH, cortisol, and DHEA levels were studied during the infusion of placebo, canrenoate, a MR antagonist (CAN, 200 mg i.v. bolus at 1600 h followed by 200 mg infused over 4 h), and human CRH (hCRH; 2.0 microg/kg i.v. bolus at 1800 h) 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 versus placebo (P<0.05). Post-treatment sessions: during placebo infusion, cortisol and DHEA were significantly amplified versus 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 with 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 activities of the HPA axis, while it blunts the HPA responsiveness to a further MR-mediated stimulation.
Berardelli
Rita
R
Division of Endocrinology, Diabetology and Metabolism, Department of Internal Medicine, University of Turin, Ospedale S. Giovanni Battista-Molinette, C.so Dogliotti 14, Turin, Italy.
Karamouzis
Ioannis
I
Marinazzo
Elisa
E
Prats
Elisa
E
Picu
Andreea
A
Giordano
Roberta
R
Ghigo
Ezio
E
Arvat
Emanuela
E
D000311:Adrenal Glands / Q000187:drug effects / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D000704:Analysis of Variance; D002191:Canrenoic Acid / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D000451:Mineralocorticoid Receptor Antagonists; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000502:physiology*
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D003687:Dehydroepiandrosterone; D002191:Canrenoic Acid; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone