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Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid

Brett M Mitchell1, Anne M Dorrance, Eniki A Mack

  • 1Department of Physiology, Medical College of Georgia, Augusta, 30912, USA. bretmitchell@hotmail.com

Journal of Cardiovascular Pharmacology
|December 12, 2003
PubMed
Summary
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Excess glucocorticoids reduce aortic dilation by decreasing GTPCH1 mRNA, a key enzyme for nitric oxide production. This effect is mediated by the glucocorticoid receptor, impacting blood vessel function.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Endocrinology

Background:

  • Glucocorticoids can negatively impact vascular function.
  • Guanylate triphosphate (GTP) cyclohydrolase 1 (GTPCH1) is crucial for tetrahydrobiopterin (BH4) synthesis, a nitric oxide synthase (NOS) cofactor.
  • The precise mechanism by which glucocorticoids affect GTPCH1 and vascular tone is not fully understood.

Purpose of the Study:

  • To investigate if glucocorticoid-induced decreases in aortic dilation and GTPCH1 expression are mediated by the glucocorticoid receptor (GR).
  • To determine the role of GR in regulating GTPCH1 mRNA levels and endothelium-dependent relaxation.

Main Methods:

  • Incubation of endothelium-intact rat aortas with dexamethasone (DEX) or vehicle.
  • Measurement of isometric force generation and acetylcholine-induced relaxation.

Related Experiment Videos

  • Assessment of GTPCH1 mRNA expression via quantitative analysis.
  • Use of GR antagonist (mifepristone) and mineralocorticoid receptor antagonist (spironolactone) for mechanistic studies.

    • Main Results:

    • Dexamethasone significantly decreased acetylcholine-induced relaxation in rat aortas after 6 hours.
    • Sepiapterin, a BH4 precursor, restored vascular relaxation, indicating a role for BH4 deficiency.
    • Dexamethasone significantly reduced GTPCH1 mRNA expression, an effect blocked by mifepristone but not spironolactone.
    • GR antagonism completely prevented the dexamethasone-induced decrease in relaxation and GTPCH1 mRNA.

    Conclusions:

    • Glucocorticoid-induced reduction in aortic dilation is linked to decreased GTPCH1 mRNA expression.
    • The glucocorticoid receptor mediates this downregulation of GTPCH1.
    • This mechanism contributes to impaired endothelium-dependent relaxation under excess glucocorticoid conditions.