Effects of sepiapterin supplementation and NOS inhibition on glucocorticoid-induced hypertension

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.MethodsMale Sprague-Dawley (SD) rats (n = 7-13\group) were treated with either sepiapterin (5mg\kg\day, IP) or saline (sham) 4 days before and during ACTH (0.2mg\kg\day, SC), dexamethasone (0.03mg\kg\day, SC), or saline treatment. NOLA (0.4mg\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.ResultsBoth ACTH (116 2 to 135 3mmHg (mean s.e.m.), P 0.001) and dexamethasone (114 4 to 133 3mmHg, P 0.0005) increased SBP. Sepiapterin alone did not alter SBP. Sepiapterin did not prevent ACTH-(129 4mmHg, NS) or dexamethasone-induced hypertension (135 3mmHg, 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 3mmHg, P 0.05) and dexamethasone-treated rats (135 5 to 170 6mmHg, P 0.05). ACTH and dexamethasone increased plasma F 2-isoprostane concentrations. Neither sepiapterin nor NOLA significantly affected this marker of oxidative stress.ConclusionSepiapterin 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.