Nitric oxide inhibits ACTH-induced cortisol production in near-term, long-term hypoxic ovine fetal adrenocortical cells

Reprod Sci. 2010 Oct;17(10):955-62. doi: 10.1177/1933719110376092. Epub 2010 Aug 16.


We previously reported that in the sheep fetus, long-term hypoxia (LTH) resulted in elevated basal plasma adrenocorticotropic hormone (ACTH(1- 39)) whereas the cortisol levels were not different from normoxic controls. We also showed that LTH enhances endothelial nitric oxide synthase (eNOS) expression in the fetal adrenal. This study was designed to determine the effect of NO on cortisol production in adrenocortical cells from LTH fetal sheep. Ewes were maintained at high altitude (3820 m) from ∼40 days' gestation (dG) to near term. Between 138 and 141 dG, fetal adrenal glands were collected from LTH and age-matched normoxic control fetuses. Adrenal cortical cells were pretreated with sodium nitroprusside (SNP), nitro-L-arginine methyl ester (L-NAME), L-arginine, or diethyleneamine NO (DETA-NO) and then challenged with 10 nmol/L ACTH. Cortisol responses were compared after 1 hour. Adrenocorticotropic hormone -induced cortisol secretion was significantly higher in LTH versus control (P < .01). Enhancement of NO with L-arginine resulted in a significant reduction of ACTH-mediated cortisol production in the LTH group. DETA-NO also caused a significant decrease in ACTH-mediated cortisol production (P < .05). Inhibition of NOS with L-NAME significantly increased cortisol production in the LTH group (P < .05 compared to ACTH alone), whereas the effect on the control group was not significant. Nitric oxide synthase activity was significantly higher in the LTH group compared to control, but this difference was eliminated following ACTH treatment. These data indicate that LTH enhances adrenal cortical sensitivity to the inhibitory effects of NO on cortisol production. Nitric oxide may, therefore, play an important role in regulating ACTH-induced cortisol production in the LTH fetal adrenal.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenal Cortex / metabolism*
  • Adrenocorticotropic Hormone / metabolism*
  • Animals
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fetal Hypoxia / metabolism*
  • Fetus
  • Hydrocortisone / analysis
  • Hydrocortisone / metabolism*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase Type III / metabolism
  • Nitroprusside / pharmacology
  • Pregnancy
  • Sheep
  • Triazenes / pharmacology


  • 1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene
  • Enzyme Inhibitors
  • Nitric Oxide Donors
  • Triazenes
  • Nitroprusside
  • Nitric Oxide
  • Adrenocorticotropic Hormone
  • Nitric Oxide Synthase Type III
  • NG-Nitroarginine Methyl Ester
  • Hydrocortisone