Endocrinology · 1998 · 161 citations · 31 references
MedicineEndocrinologyPharmacologyNeuroendocrinologyNeuropharmacologySteroid BiochemistryAdrenal Axis RegulationAdrenal HormonesAdrenal Steroid HormonesHypothalamic-pituitary RegulationStress EndocrinologyStress Hormone RegulationCorticosteroid Receptor SelectivityCorticosteroid RegulationGlucocorticoid Feedback MechanismsGlucocorticoid Feedback RegulationGlucocorticoid ReceptorsHpa Axis ActivityHypothalamic-pituitary-adrenal FeedbackRestraint Stress
The study investigated how mineralocorticoid and glucocorticoid receptors mediate corticosteroid feedback on the HPA axis. RU28318 selectively occupied ~85% of brain mineralocorticoid receptors, whereas RU40555 occupied ~50% of glucocorticoid receptors. Blocking mineralocorticoid receptors increased morning basal corticosterone, glucocorticoid blockade alone had no effect, but combined blockade raised evening basal and stress‑induced corticosterone and ACTH, showing that mineralocorticoid activation is necessary for low basal levels and facilitates glucocorticoid‑dependent suppression during peaks and stress.
These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.
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Primary structure and expression of a functional human glucocorticoid receptor cDNA
Stanley M. Hollenberg, Cary Weinberger, Estelita S. Ong et al. · Nature · 1985 · 1.9K citations · Full text