Objective: To determine basic vascular response and to clarify the mechanisms of flow-induced dilatation (FID) of middle cerebral artery (MCA) of Sprague-Dawley (SD) rats on a high salt (HS) diet by expression of the essential antioxidant genes, genes involved in the dilation pathways , level of leukocyte activation and the role of oxidative stress. Methods: 11-weeks old healthy male SD rats were divided in low salt group (LS) fed with standars rat chow (0.4% NaCl) and high salt group (HS fed food with 4% NaCl) for 1 week with/without addition TEMPOL in vivo. Vascular reactivity of MCA in response to FID in the absence/presence of inhibitors of the nitric oxide synthase (NOS) (L-NAME), cyclooxygenase 1 and 2 (COX-1,2) indomethacin (INDO), selective inhibitor of microsomal CYP450 epoxidase activity (MS-PPOH) and superoxide dismutase (SOD) mimetic TEMPOL was examined. mRNA levels of antioxidative enzymes (SOD isoforms, glutathione peroxidases (GPx 1 and GPx4), catalase (CAT)) and enzymes involved in dilatation pathways of MCA (COX-1, 2, hypoxia-induced factor 1 alpha (HIF- 1α), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and HIF prolyl hydroxylases isoforms) were determined by quantitative real-time PCR from brain blood vessels. Relations of helper and cytotoxic T lymphocytes, activated regulatory Foxp3 helper T lymphocytes and level of oxidative stress in leukocytes from the blood and peripheral organs were examined by flow cytometry. Blood pressure, lipid peroxidation products and antioxidant capacity of plasma were measured for both groups. Results: FID was reduced in HS group compared to LS group. L-NAME, INDO and MS-PPOH (independantly) significantly reduced FID in LS group, FID in HS group was mediated by NO. TEMPOL restored FID in HS group to basal levels while in LS group TEMPOL had no effect. Expression of GPx4 and iNOS in HS group was significantly decreased. HS intake significantly increased basic reactive oxygen species production in the leukocytes of mesenteric lymph nodes and spleenocytes, and intracellular production after stimulation in peripheral lymph nodes. Antioxidant enzymes activity and BP were not affected by HS diet. Conclusion: HS intake impaires vascular responses to FID. These data for the first time show that mechanisms of FID are different in LS and HS groups. Low GPx4 expression, increased superoxide production in leukocytes, together with decreased iNOS expression underlies increased oxidative stress and reduced nitric oxide bioavailability in HS group, which caused impairment of FID in HS group without changes in BP values.