Salt sensitivity, described as association between salt intake and blood pressure (BP), varies among individuals. Traditional views on salt induced hypertension has been focused on the kidney and extracellular volume expansion. Recent studies have provided new insights linking dietary salt, inflammation and defective sodium sensing in brain. The hypothalamus in particular are intricately involved in the pathogenesis of sympathetic mediated hypertension. Ion channel function has been proposed to contribute to hypothalamic-driven sympathetic activity. Our aim was to examine if modest BP elevation observed in normotensive male Wistar rats after exposure to high salt diet could be at least in part mediated by alterations in the availability and/or action of sodium (Na+) in the hypothalamus. Blood pressure (BP) was recorded in male Wistar rats ( 3 months of age) after 2 weeks of low salt diet (LSD, 0.1% NaCl, n=6) or high salt diet (HSD, 8% NaCl, n=6) using radio-telemetry (DSI Instruments). Osmolality and electrolyte content were measured in the cerebrospinal fluid (CSF) and hypothalamus using osmometer and HPLC respectively. Endogenous Ouabain (soluble inhibitor of the sodium pump Na+/K+ ATPase) was measured in plasma, CSF and hypothalamus using ELISA (Lifeome). Hypothalamic ion channels including the voltage-gated sodium channel (Nax-SCN7a) and epithelial sodium channel (ENAc) were identified using immunohistochemistry (anti-rabbit ENAc, anti-rabbit Nax, anti-mouse Abcam; GFAP, anti-mouse NeuN Novus) and semi-quantified using QPCR Primers:NaxF-AAACTCGAGAGGACCTGAACC,NaxR-TTTTTATCAAAGCTCTCAGAA CCAC; ENAcF-ACTGTCTGCACCCTTAATCCTT ENAcR-GTGATGCGGTCCAGCTCT. Only a modest increase in systolic BP (HSD, 130±2 versus LSD, 126±3 mmHg, P=0.07, n=6) was noted after two weeks of HSD. The HSD rats demonstrated increased (Na+) and Ouabain in the CSF (P<0.05) and hypothalamus (P<0.05) with no effect on CSF osmolality or plasma Ouabain. Nax immunostaining in the PVN (hypothalamus) showed no effect on the cellular phenotype between HSD and LSD. Nax immunostaining was not co-localized with NeuN (neuron-marker) or GFAP (astrocyte marker) immunostaining. Relative quantitative PCR demonstrated a 2 fold increase in hypothalamic Nax mRNA and ENAc mRNA in HSD versus LSD. Nax mRNA expression was positive correlated with the systolic BP (r=0.62, P<0.05). In conclusion, hypothalamic sodium channels may be involved in salt sensitivity, highlighting recent finding that HSD cause sodium imbalance in the hypothalamus which long term recruit pro-hypertensive via sympathoexcitatory neural mechanism.