Glucocorticoids act rapidly in vitro to attenuate second messenger responses to ACTH secretagogues in rats.
Fragments of rat anterior pituitary glands incubated in vitro and challenged with either of two ACTH secretagogues were used to investigate the extent to which the acute, biphasic, feedback-like inhibitory effects on hormone secretion exerted by the synthetic glucocorticoid dexamethasone were related to alterations in second messenger responses. Addition of dexamethasone was shown to cause both an immediate inhibition (fast inhibition) of the release of ACTH-like immunoreactivity induced by arginine vasopressin (AVP) or corticotrophin-releasing factor (CRF-41), and also an inhibition that occurred after removal of the steroid and was maximal 90 min after its introduction (early delayed inhibition). The accumulation of adenosine 3',5'-monophosphate (cAMP) in the tissue was enhanced in a dose-related manner by CRF-41, as was that of phosphate esters of inositol (inositol phosphates) by AVP. The dose-response curve for the effect of CRF-41 on cAMP production was markedly shifted to the right by dexamethasone acting in the time-domain of fast inhibition (i.e. the response was attenuated, but not abolished). Application of the steroid during the same time-period reduced significantly the inositol phosphate response induced by the higher concentration of AVP tested (3000 nmol/l), but had no effect on the action of a lower concentration (30 nmol/l). In contrast, the cAMP and inositol phosphate dose-response curves to CRF-41 and AVP respectively were unaffected by the glucocorticoid when it was applied at the time which generated early delayed inhibition of ACTH release.(ABSTRACT TRUNCATED AT 250 WORDS)
Nicholson
S A
SA
Division of Physiology, Guy's Campus, United Medical and Dental Schools, University of London.
Gillham
B
B
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005246:Feedback; D005260:Female; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010902:Pituitary Gland / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D015290:Second Messenger Systems / Q000187:drug effects*; D013997:Time Factors
D010446:Peptide Fragments; D001127:Arginine Vasopressin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; C045089:corticotropin releasing hormone (9-41); D000242:Cyclic AMP