Increased neuroendocrine reactivity and decreased brain mineralocorticoid receptor-binding capacity in aged dogs.
The effects of aging on the regulation of the hypothalamus-pituitary-adrenocortical (HPA) system of the dog were investigated. For this purpose, we compared 11 healthy dogs, 11-14 yr old, with 14 young mature dogs, 18-24 months of age. Significantly higher basal HPA activity in the old dogs was indicated by their higher resting plasma concentrations of ACTH, alpha MSH, and cortisol over a 6-week period and higher cortisol excretion in 24-h urine. After stress by immobilization as well as by light electric foot shocks and after i.v. administration of 1 microgram/kg CRH, the old dogs had higher peak levels of ACTH and cortisol, but not of alpha MSH. The areas under the curve, corrected for the basal levels, for ACTH and cortisol after these challenges were also greater in the old dogs. The half-times to reach a 50% increment and a 50% decrement in the time-concentration curves of ACTH and cortisol were similar in old and young dogs. There were no differences between the old and young dogs in their response to i.v. administration of 0.01 mg/kg dexamethasone. The clearance of [14C]cortisol from plasma, as calculated in a two-compartment model, was significantly reduced in aged dogs. In the old dogs, the stress- and CRH-induced cortisol peaks were relatively higher than those of ACTH, and their adrenals weighed significantly more, suggesting chronic hyperadrenocorticotropism. Aging had a markedly different effect on the two types of corticosteroid receptors in brain and pituitary. The binding capacity of type II or glucocorticoid receptors (GRs) in the old dogs was unchanged compared with that in the young dogs in all investigated brain structures except the anterior pituitary, in which the number of GRs was increased up to 170%. Type I or mineralocorticoid receptor (MR)-binding capacity was largely decreased in the brain of old dogs. The MR levels in old dogs, expressed as a percentage of the corresponding levels in young dogs, were 34% in the dorsal hippocampus, 58% in the ventral hippocampus, 37% in the septum, and 54% in the hypothalamus. In the anterior pituitary, MR capacity was unchanged. There was no difference between Kd values of MR and GR binding in young and old dogs. We conclude that these aged dogs had elevated basal HPA activity, characterized by increased levels of basal ACTH and cortisol in plasma and of urinary cortisol excretion and by hyperreactivity of ACTH and cortisol secretion in response to challenge by stress or CRH.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Clinical Sciences of Companion Animals, University of Utrecht, The Netherlands.
J
J
Rothuizen
J M
JM
Reul
F J
FJ
van Sluijs
J A
JA
Mol
A
A
Rijnberk
E R
ER
de Kloet
D000302:Adrenal Cortex / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004285:Dogs / Q000502:physiology*; D005246:Feedback; D005260:Female; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D007031:Hypothalamus / Q000502:physiology*; D008297:Male; D010902:Pituitary Gland / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000378:metabolism*; D000521:alpha-MSH / Q000097:blood
D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D000521:alpha-MSH; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone