title: Effects of sepiapterin supplementation and NOS inhibition on glucocorticoid-induced hypertension.
abstract: BACKGROUND
  Glucocorticoid-induced hypertension is associated with imbalance between nitric oxide (NO) and superoxide. One of the pathways that causes this imbalance is endothelial NO synthase (eNOS) uncoupling. In the present study, adrenocorticotrophic hormone (ACTH)- and dexamethasone-treated rats were further treated with sepiapterin, a precursor of tetrahydrobiopterin, or N-nitro-L-arginine (NOLA), an inhibitor of NOS, to investigate the role of eNOS uncoupling in glucocorticoid-induced hypertension.
  
  
  METHODS
  Male Sprague-Dawley (SD) rats (n = 7-13/group) were treated with either sepiapterin (5 mg/kg/day, IP) or saline (sham) 4 days before and during ACTH (0.2 mg/kg/day, SC), dexamethasone (0.03 mg/kg/day, SC), or saline treatment. NOLA (0.4 mg/ml in drinking water) was given to rats 4 days before and during dexamethasone treatment. Systolic blood pressure (SBP) was measured by the tail-cuff method.
  
  
  RESULTS
  Both ACTH (116 +/- 2 to 135 +/- 3 mm Hg (mean +/- s.e.m.), P < 0.001) and dexamethasone (114 +/- 4 to 133 +/- 3 mm Hg, P < 0.0005) increased SBP. Sepiapterin alone did not alter SBP. Sepiapterin did not prevent ACTH- (129 +/- 4 mm Hg, NS) or dexamethasone-induced hypertension (135 +/- 3 mm Hg, NS), although plasma total biopterin concentrations were increased. NOLA increased SBP in rats prior to dexamethasone or saline treatment. NOLA further increased SBP in both saline- (133 +/- 4 to 157 +/- 3 mm Hg, P < 0.05) and dexamethasone-treated rats (135 +/- 5 to 170 +/- 6 mm Hg, P < 0.05). ACTH and dexamethasone increased plasma F(2)-isoprostane concentrations. Neither sepiapterin nor NOLA significantly affected this marker of oxidative stress.
  
  
  CONCLUSIONS
  Sepiapterin did not prevent ACTH- or dexamethasone-induced hypertension. NOLA exacerbated dexamethasone-induced hypertension. These data suggest that eNOS uncoupling does not play a major role in the genesis of glucocorticoid-induced hypertension in the rat.
authors.affiliation: The High Blood Pressure Research Unit, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors.forename: Mya
authors.initials: M
authors.lastname: Thida
authors.forename: John
authors.initials: J
authors.lastname: Earl
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hans
authors.initials: H
authors.lastname: Wang
authors.forename: Chi S
authors.initials: CS
authors.lastname: Tse
authors.forename: Janine J
authors.initials: JJ
authors.lastname: Vickers
authors.forename: Matthew
authors.initials: M
authors.lastname: Sutton
authors.forename: Sharon L H
authors.initials: SL
authors.lastname: Ong
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Mori
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Judith A
authors.initials: JA
authors.lastname: Whitworth
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001708:Biopterins / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D028441:F2-Isoprostanes / Q000097:blood; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress; D011622:Pterins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D011622:Pterins; D019335:Nitroarginine; D001708:Biopterins; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III