Intracerebroventricularly infused hypertonic saline elicits sympathoexcitatory and pressor effects. To clarify the mechanisms mediating these effects, we evaluated blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to intracerebroventricular administration of 0.3 M NaCl, ouabain, and rat hypothalamic and pituitary extracts containing ouabain-like activity (OLA) in conscious Wistar rats, before and after intracerebroventricular preinjection of digoxin-specific antibody Fab (DAF) fragments. To exclude modulatory effects of arginine vasopressin (AVP), treatment with DAF fragments was in all experiments preceded by intravenous injection of the AVP antagonist [β-mercapto-β,β-cyclopentamethylenepropionyl1,o-Me-Tyr2,Arg8]AVP. After AVP antagonist pretreatment, 0.3 M NaCl i.c.v. at 3.8 μl/min for 10 minutes caused simultaneous increases in BP, RSNA, and HR. After AVP antagonist pretreatment, intracerebroventricular injections of 0.3 and 1.0 μ/l μl ouabain or the OLA equivalent to 1 μg ouabain/2 μl elicited similar significant increases in BP, HR, and RSNA. After pretreatment with AVP antagonist and DAF fragments (66 μg/4 μl i.c.v.), BP, HR, and RSNA responses to 0.3 M NaCl, ouabain, and OLA were all significantly diminished. In contrast, combined AVP blockade and DAF fragments did not affect the BP response to intracerebroventricular angiotensin II, the BP, HR, and RSNA responses to intracerebroventricular carbachol and to air stress, or the HR and RSNA responses to intravenous sodium nitroprusside. Intracerebroventricularly injected γ-globulins (66 μg/4 μl) did not affect the responses to 0.3 M NaCl, ouabain, or OLA. These data demonstrate that the effects of intracerebroventricularly infused hypertonic saline share, at least in part, a common mechanism with the effects of intracerebroventricular ouabain/OLA; i.e., brain OLA appears to be involved in the sympathoexcitatory and pressor effects of intracerebroventricular hypertonic saline.