Inactivation of early glucocorticoid feedback by corticotropin-releasing factor in vitro.
We have investigated the interaction between hypothalamic ACTH secretagogues and adrenocortical glucocorticoids in rat anterior pituitary tissue using an in vitro perifusion system. Repeated 5 min pulses of 41-residue CRF (CRF-41) or arginine vasopressin (AVP) were applied at 1 h intervals for up to 7 h. Administration of 0.1 microM corticosterone 30 min before and during the 5 min 0.1 nM CRF-41 stimulus at 5 h resulted in a significant inhibition of CRF-41 stimulated ACTH release within 30 min. Inhibition of ACTH release also developed if no CRF-41 stimulus was applied in conjunction with steroid at 5 h. In contrast, if the exposure to corticosterone (0.1 microM, 35 min total duration) was started simultaneously with the application of CRF-41 at 5 h, no inhibition of ACTH release ensued. Similarly, no inhibition of CRF-41-stimulated ACTH release was observed when corticosterone was started simultaneously with a 5 min pulse of cyclic 8-(4-Chlorophenylthio) AMP (8-CPT-cAMP), a cell membrane permeant analog of cAMP. In contrast to CRF-41 and 8-CPT-cAMP, AVP failed to modify glucocorticoid-induced inhibition of AVP- or CRF-41-stimulated ACTH release. Moreover, CRF-41 did not prevent the glucocorticoid-induced inhibition of AVP-stimulated ACTH release. In summary: 1) CRF-41 inactivates early glucocorticoid inhibition of CRF-41-stimulated ACTH secretion, and this is mimicked by a cell membrane permeant analog of cAMP; 2) AVP does not inactivate glucocorticoid-induced inhibition of stimulated ACTH release; 3) the data point to an acute interaction between the cAMP/protein kinase A and glucocorticoid-responsive intracellular pathways. Such differential modulation of feedback inhibition by CRFs may be of functional importance in vivo.
Shipston
M J
MJ
Medical Research Council Brain Metabolism Unit, University Department of Pharmacology, Edinburgh, Scotland.
Antoni
F A
FA
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D005246:Feedback; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D010477:Perfusion; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D005938:Glucocorticoids; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone