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Effect of a melanocortin type 2 receptor (MC2R) antagonist on the corticosterone response to hypoxia and ACTH stimulation in the neonatal rat. Am J Physiol Regul Integr Comp Physiol 2018 07 01;315(1):R128-R133

Date

05/03/2018

Pubmed ID

29718699

Pubmed Central ID

PMC6087887

DOI

10.1152/ajpregu.00009.2018

Scopus ID

2-s2.0-85051268792   2 Citations

Abstract

The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, nonimmunoreactive ligand to the melanocortin type 2 receptor (MC2R). GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or vehicle for GPS1574 in PD2, PD8, and PD15 rat pups. Pretreatment with GPS1574 decreased baseline corticosterone in PD2 pups but increased baseline corticosterone in PD8 and PD15 pups. GPS1574 did not attenuate the corticosterone response to hypoxia in PD2 pups and augmented the corticosterone response in PD8 and PD15 pups. GPS1574 augmented the corticosterone response to ACTH in PD2 and PD15 pups but had no significant impact on the response in PD8 pups. Baseline adrenal Mrap and Star mRNA increased from PD2 to PD15, whereas Mrap2 mRNA expression was low and did not change with age. The data suggest that GPS1574 is not a pure MC2R antagonist, but rather acts as a biasing agonist/antagonist. Its ability to attenuate or augment the adrenal response may depend on the ambient plasma ACTH concentration and/or developmental changes in early transduction steroidogenic pathway genes.

Author List

Goldenberg AJ, Gehrand AL, Waples E, Jablonski M, Hoeynck B, Raff H

Author

Hershel Raff PhD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adrenal Glands
Adrenocorticotropic Hormone
Age Factors
Animals
Animals, Newborn
Biomarkers
Corticosterone
Disease Models, Animal
Gene Expression Regulation
Hormone Antagonists
Hypoxia
Phosphoproteins
Rats, Sprague-Dawley
Receptor, Melanocortin, Type 2
Stress, Physiological
Time Factors
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d