Endocrinology, Vol 125, 308-313, Copyright © 1989 by Endocrine Society

ARTICLES

Rapid as well as delayed inhibitory effects of glucocorticoid hormones on pituitary adrenocorticotropic hormone release are mediated by type II glucocorticoid receptors and require newly synthesized messenger ribonucleic acid as well as protein

G Dayanithi and FA Antoni
Department of Human Anatomy, University of Oxford, England.

Glucocorticoid hormones suppress the release of ACTH by the anterior pituitary gland: rapid feedback inhibits hormone secretion within 30 min of steroid application, delayed feedback is most effective at 1-2 h, and slow feedback becomes manifest in several hours. The aim of the present study was to determine the type of glucocorticoid receptor that mediates the rapid and delayed feedback actions of glucocorticoids and whether genomic activation occurs during the rapid and delayed time domains. Rat anterior pituitary cell columns were perfused with Dulbecco's minimum essential medium, 41-residue CRF (10(-9) M) was used as the secretagogue, which stimulated ACTH secretion to a peak of about 8- to 10-fold of basal release. The amount of ACTH released upon repeated 5 or 10 min stimulation with CRF was constant. Treatment with 10(-7) M corticosterone for 20 min immediately before and for 10 min during stimulation with CRF reduced ACTH release by about 50% (rapid feedback), while at 1 h and 2 h after the initial exposure to corticosterone the secretory response was 33% and 15% of control, respectively. The effect of corticosterone was prevented by the type II glucocorticoid/progesterone antagonist RU 38486 (10(-6) M). The selective type II receptor agonist RU 28362 (10(-7) M) was even more potent than corticosterone in inhibiting ACTH release; the time course of action was similar. When actinomycin D (10(-4) M) was applied in conjunction with RU28362 or corticosterone, no inhibitory effects appeared up to 2 h after the exposure to steroid. Puromycin (10(-4) M), given during and for 1 h after the administration of the steroid prevented the rapid as well as the delayed (1 h) inhibitory action of RU28362. When puromycin was removed from the system, a 75% inhibition of stimulated ACTH release developed at 2 h after the application of the steroid, indicating that translatable messenger RNA (mRNA) was still present in the cells. Cycloheximide (10(-4) M) was only partially effective at inhibiting rapid or delayed feedback, and increasing its concentration impaired the ACTH response to CRF-41. In summary, at the pituitary level the rapid as well as the delayed feedback inhibition of ACTH secretion by adrenal corticoids is exerted via type II glucocorticoid receptors. Furthermore, both rapid and delayed feedback require the synthesis of new mRNA and protein.

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