Pharmacological evidence that the inhibition of diurnal adrenocorticotropin secretion by corticosteroids is mediated via type I corticosterone-preferring receptors.
These studies were performed to determine pharmacologically the corticosteroid receptor type that mediates the effects of corticosterone (B) on ACTH secretion in adrenalectomized rats. We have compared the effects of treating young male rats at the time of adrenalectomy and throughout the next 5 days with B, dexamethasone (DEX), or aldosterone (ALDO) in doses that elevated plasma levels to concentrations in the range between 0.2-30 nM. Plasma ACTH, corticosteroid-binding globulin (CBG), and thymus weight were measured in the morning or evening, and these steroid-sensitive end points were related to the circulating concentrations of B (total B - CBG-bound B), total DEX, and total ALDO. For the inhibition of ACTH the rank order of potency of the three steroids was B greater than DEX greater than or equal to ALDO in the morning (estimated IC50, 0.7 +/- 0.1, 2.3 +/- 0.5, and 4.9 +/- 1.6 nM for B, DEX, and ALDO, respectively). There was a significant shift to the right in steroid efficacy between morning and evening (estimated IC50 in the evening, 3.9 +/- 0.2 and 9.3 +/- 0.8 nM for B and DEX; ALDO at the concentrations achieved was ineffective). The rightward shift in efficacy may result from the circadian increase in drive to ACTH secretion. The rank order of potency for B and DEX on ACTH and the agreement between the steady state IC50 values achieved for these steroids and the Kd values determined for B and DEX with type I receptors in vitro strongly suggest that feedback control of basal diurnal ACTH by corticosteroids is mediated by association with type I, B-preferring receptors. By contrast, DEX was 3 times more potent than B on CBG (estimated IC50, 1.5 and 4.5 nM, respectively) and tended to be more effective on thymus weight, suggesting that the effects of corticosteroids on these peripheral targets are mediated by association of the steroids with type II glucocorticoid receptors. ALDO coinfused with DEX or B did not alter the inhibitory effects of these on ACTH, suggesting that ALDO does not interfere with these type I, B-preferring receptors in vivo. Because there is little if any evidence for type I corticosteroid receptors in the hypothalamus, these results strongly suggest that the majority of corticosteroid feedback inhibition of basal morning and evening ACTH secretion is mediated transynaptically by the activity of extra-hypothalamic neurons.
Dallman
M F
MF
Department of Physiology and Obstetrics, University of California, San Francisco 94143.
Levin
N
N
Cascio
C S
CS
Akana
S F
SF
Jacobson
L
L
Kuhn
R W
RW
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects*; D003345:Corticosterone / Q000494:pharmacology* / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D007016:Hypophysectomy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D011987:Receptors, Steroid; D012016:Reference Values; D014156:Transcortin / Q000378:metabolism
D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; C024357:corticosterone receptor; D000450:Aldosterone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D014156:Transcortin; D003345:Corticosterone