Hypertonic NaCl infused into the carotid arteries increases arterial blood pressure (AP) and changes sympathetic nerve activity (SNA) via cerebral mechanisms. We hypothesized that elevated sodium levels in the blood supply to the brain would induce differential responses in renal and cardiac SNA via sensors located outside the blood-brain barrier. To investigate this hypothesis we measured renal and cardiac SNA simultaneously in conscious sheep during intracarotid (IC) infusions of NaCl (1.2 M), sorbitol (2.4 M) or urea (2.4 M) at 1 mL/min up each carotid. IC NaCl significantly increased AP (91±2 to 97±3 mmHg, p<0.05) without changing heart rate (HR). IC NaCl was associated with no change in cardiac SNA (11±5.0%), but a significant inhibition of renal SNA (-32.5±6.4%, p<0.05). Neither IC sorbitol nor urea changed AP, HR, CVP or cardiac and renal SNA. The changes in AP and renal SNA were completely abolished by microinjection of the GABA agonist muscimol (5mM, 500nL) into the paraventricular nucleus of the hypothalamus (PVN). Infusion of IC NaCl for 20 min stimulated a larger increase in water intake (1100±75 mL) than IC sorbitol (683±125 mL) or IC urea (0 mL). These results demonstrate that acute increases in blood sodium levels cause a decrease in renal but no change in cardiac SNA in conscious sheep. These effects are mediated by cerebral sensors located outside the blood-brain barrier that are more responsive to changes in sodium concentration than osmolality. The renal sympatho-inhibitory effects of sodium are mediated via a pathway that synapses in the PVN.