Functional studies indicate that the sympatho-excitatory and pressor responses to an increase in CSF [Na⁺] by central infusion of Na⁺-rich artificial cerebrospinal fluid (aCSF) in Wistar rats are mediated in the brain by mineralocorticoid receptor (MR) activation, ouabain-like compounds (OLC) and AT₁-receptor stimulation. In the present study, we examined whether increasing CSF [Na⁺] by icv infusion of Na⁺-rich aCSF activates MR and thereby increases OLC and components of the renin-angiotensin system in the brain. Male Wistar rats received via osmotic minipump an icv infusion of aCSF or Na⁺-rich aCSF, in some groups combined with icv infusion of spironolactone (100 ng/hr), antibody Fab fragments (to bind OLC) or as control -globulins. After 2 wks of infusion, resting BP and HR were recorded, OLC and aldosterone content in the hypothalamus were assessed by a specific ELISA or radio-immunoassay, and angiotensin-converting enzyme (ACE) and AT₁-receptor binding densities in various brain nuclei measured by autoradiography using ¹²⁵I-labelled 351 A and ¹²⁵I-labelled Ang II. Compared to icv aCSF, icv Na⁺-rich aCSF increased CSF [Na⁺] by ~5 mmol/L, MAP by ~20 mmHg, HR by ~65 bpm, and hypothalamic content of OLC by 50% and of aldosterone by 33%. Icv spironolactone did not affect CSF [Na⁺], but blocked the Na⁺- rich aCSF induced increases in BP and HR and OLC content. Icv Na⁺-rich aCSF increased ACE and AT₁-receptor binding densities in several brain nuclei, and Fab fragments blocked these increases. These data indicate that in Wistar rats, a chronic increase in CSF [Na⁺] may increase hypothalamic aldosterone and activates CNS pathways involving MR, and OLC, leading to increases in AT₁-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension.