To investigate the effect of folic acid on the increased pressure in rats treated with either adrenocorticotropic hormone (ACTH) or dexamethasone (Dex), and to further investigate the role of tetrahydrobiopterin (BH4) in any effect of folic acid by comparing the effect of BH4 with that of folic acid in Dex hypertension.Methods: Male Sprague-Dawley (SD) rats were treated with saline, subcutaneous ACTH (0.2 mg/kg/d) or Dex (10 μg/rat/d). Folic acid (0.04 g/L drinking) or BH4 (10 mg/kg/d intraperitoneally) was started before (prevention) and during (reversal) glucocorticoid treatment.Results: Saline, BH4, vehicle for BH4, or folic acid alone did not change systolic blood pressure (BP). Systolic BP was increased by ACTH and Dex. Folic acid, but not BH4, prevented the development of hypertension caused by ACTH and Dex treatment. The ACTH and Dex hypertension were partially reversed by folic acid. The BH4 increased plasma total biopterin concentrations. The Dex decreased plasma NOx concentrations but had no effect on plasma biopterin concentrations. The ACTH and Dex increased plasma F2-isoprostane concentrations and decreased serum homocysteine concentrations compared with control but had no effect on serum folate concentrations. Folic acid increased serum folate concentrations compared with control but had no effect on homocysteine concentrations.Conclusions: Folic acid prevented and partially reversed both ACTH and Dex hypertension in rats without modifying the increase in plasma F2-isoprostane concentrations. Given that BH4 failed to prevent ACTH or Dex hypertension, folic acid is unlikely to be acting through increased BH4 production. The precise mechanism for the BP-lowering effect of folic acid in this model of hypertension remains to be determined.