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1 Endocrine and 4 Transplant Research Laboratories, St. Luke's Medical Center, Milwaukee; and 2 Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53215; and 3 Department of Biology, Boston University, Boston, Massachusetts 02215
The adrenocortical
response to hypoxia may be a critical component of the adaptation to
this common neonatal stress. Little is known about adrenal function in
vivo in hypoxic neonates. The purpose of this study was to evaluate
adrenocortical responses to ACTH in suckling rat pups exposed to
hypoxia from birth to 5-7 days of age compared with normoxic
controls. We also evaluated potential cellular controllers of
steroidogenic function in situ. In 7-day-old pups at 0800, hypoxia from
birth resulted in increased basal (12.2 ± 1.4 ng/ml;
n = 12) and ACTH-stimulated (94.0 ± 9.4 ng/ml;
n = 14) corticosterone levels compared with normoxic
controls (basal = 8.3 ± 0.5 ng/ml; n = 11;
stimulated = 51.3 ± 3.8 ng/ml; n = 8). This
augmentation occurred despite no significant difference in plasma ACTH
levels in normoxic vs. hypoxic pups before (85 ± 4 vs. 78 ± 8 pg/ml) or after (481 ± 73 vs. 498 ± 52 pg/ml) porcine ACTH injection (20 µg/kg). This effect was similar in the afternoon at 6 days of age and even greater at 5 days of age at 0800. The aldosterone response to ACTH was not augmented by exposure to hypoxia
from birth. Adrenocortical hypoxia-inducible factor (HIF)-1
mRNA was
undetectable by RT-PCR. Steroidogenic acute regulatory (StAR) protein
in adrenal subcapsules (zona fasciculata/reticularis) was augmented by
exposure to hypoxia; this effect was greatest at 5 days of age.
Peripheral-type benzodiazepine receptor (PBR) protein was also
increased at 6 and 7 days of age in pups exposed to hypoxia from birth.
We conclude that hypoxia from birth results in an augmentation of the
corticosterone but not aldosterone response to ACTH. This effect
appears to be mediated at least in part by an increase in controllers
of mitochondrial cholesterol transport (StAR and PBR) and to occur
independently of measurable changes in endogenous plasma ACTH. The
augmentation of the corticosterone response to acute increases in ACTH
in hypoxic pups is likely to be an important component of the overall
physiological adaptation to hypoxia in the neonate.
adrenocorticotropin; aldosterone; newborn; steroidogenic acute regulatory protein; peripheral-type benzodiazepine receptor; hypoxia-inducible factor
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