The contribution of the paraventricular nucleus of the hypothalamus (PVN) in mediating cardiovascular, renal, hormonal and sympathetic nerve responses to increased cerebrospinal fluid (CSF) [Na⁺] was investigated in conscious sheep. ICV hypertonic NaCl (0.5 mol/L, 20 µL/min for 60 min) increased arterial blood pressure (+13.4 mmHg SD 2.0, P<0.001, AP) and central venous pressure (+2.8 mmHg SD 1.3, P<0.001, CVP), but did not significantly change heart rate or cardiac output (n=6). Elevated CSF-[Na⁺] also lowered plasma angiotensin II levels (-3.3 SD 1.6 pmol/L, P=0.004, Ang II), and increased creatinine clearance (+31.5 SD 32.7 ml/min, P=0.03) and renal sodium excretion (+9.2 SD 9.2 mmol/h, P=0.003). Lidocaine injection (1µL, 2%) into the PVN prior to the ICV infusion had no apparent effect, but it abolished the AP, CVP, creatinine clearance and Ang II responses to hypertonic NaCl, as well as reducing the increase in renal sodium excretion (n=6). Subsequent studies were performed in conscious sheep with chronically implanted electrodes for measurement of renal sympathetic nerve activity (RSNA). The effects of ICV hypertonic NaCl on AP and RSNA were measured before and after PVN-injection of glycine (250 nmol in 500 nL aCSF). ICV NaCl increased AP and decreased RSNA (P<0.001). These effects were significantly reduced by glycine (P=0.02-0.001, n=5). Saline injected in the PVN (n=5) or lidocaine injected outside the PVN (n=6) had no effect on the response to ICV hypertonic NaCl. These results indicate that the PVN is an important mediator of cerebrally induced homeostatic responses to elevated sodium concentration/hyperosmolality.