Studies on the mechanism of corticotrophin-mediated desensitization of corticosterone secretion by rat adrenocortical cells.
Long-term exposure of the adrenocortical cells in vivo or in vitro to high concentrations of ACTH results in a diminution of the responsiveness of these cells to a subsequent stimulation of corticosterone release by ACTH. Conflicting studies have been published on the mechanism of this 'desensitization' phenomenon. Dispersed adrenocortical cells prepared from the hypertrophic/hyperplastic adrenal glands of rats bearing the ACTH/PRL-secreting rat pituitary tumour 7315a showed an increased basal release of corticosterone, but had lost their ability to respond further to ACTH. However, corticosterone release in response to dibutyryl cyclic AMP (dbcAMP), cholera toxin and forskolin remained intact. Pretreatment of normal rats for 3, 9 and 21 days with 50 micrograms/rat/day of a long-acting ACTH depot preparation induced a dose-dependent increase in basal corticosterone release by the adrenocortical cells prepared from these animals and a dose-dependent decrease in the sensitivity to ACTH. However, the responsiveness of the adrenocortical cells prepared from the adrenal glands of control and ACTH pretreatment rats to dbcAMP, cholera toxin and forskolin was similar. In addition, pretreatment with ACTH in vivo did not affect the sensitivity of the adrenocortical cells in vitro to calmodulin inhibition by haloperidol and 11 beta-hydroxylase inhibition by etomidate. It is concluded that long-term exposure of the adrenal gland to high concentrations of ACTH in vitro results in an excessive activation of corticosterone release by the adrenocortical cells in vitro, which is accompanied by a loss of sensitivity to ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)
Lamberts
S W
SW
Department of Medicine, Erasmus University, Rotterdam, The Netherlands.
Bons
E G
EG
Zuiderwijk-van der Roest
J M
JM
D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism*; D004351:Drug Resistance; D006965:Hyperplasia; D006984:Hypertrophy; D066298:In Vitro Techniques; D010911:Pituitary Neoplasms / Q000378:metabolism; D051381:Rats; D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone / Q000187:drug effects / Q000378:metabolism
D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone; D005576:Colforsin; D003994:Bucladesine; D000324:Adrenocorticotropic Hormone; D002772:Cholera Toxin; D003345:Corticosterone