Effects of sepiapterin supplementation and NOS inhibition on glucocorticoid-induced hypertension.
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.
Thida
Mya
M
The High Blood Pressure Research Unit, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
Earl
John
J
Zhao
Yan
Y
Wang
Hans
H
Tse
Chi S
CS
Vickers
Janine J
JJ
Sutton
Matthew
M
Ong
Sharon L H
SL
Mori
Trevor A
TA
Croft
Kevin D
KD
Whitworth
Judith A
JA
Zhang
Yi
Y
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
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