The i.v. infusion of hypertonic NaCl solutions, as in small volume hypertonic NaCl resuscitation, improves cardiovascular function in hypovolemic shock. The mechanism(s) of action of this treatment is(are) not fully elucidated. In this study, we investigate the possible importance of fully functional neurocardiovascular regulation for the effect of intracerebroventricular (i.c.v.) and i.v. administration of hypertonic NaCl on the hemodynamic responses to hemorrhage. Six groups (each n = 6) of adult ewes were subjected to hypotensive hemorrhage during treatment with i.c.v. infusion (20 microL/min) of either artificial cerebrospinal fluid (controls) or 0.5 mol/L NaCl, or i.v. infusion of 1.2 mol/L NaCl (4 mL/kg) when conscious, respectively anesthetized with isoflurane. Thirty minutes into infusion, treatment blood was withdrawn at 0.7 mL/kg per minute from a jugular vein until the mean arterial pressure dropped to a value just below 50 mmHg. In conscious animals, the amount of blood loss needed to lower the mean arterial pressure to less than 50 mmHg was increased by the i.c.v. and i.v. infusions of hypertonic NaCl (24.0 +/- 4.6 and 22.4 +/- 3.3 mL/kg, respectively), compared with controls receiving i.c.v. infusion of artificial cerebrospinal fluid (14.2 +/- 1.4 mL/kg). Isoflurane anesthesia, as such, severely compromised the cardiovascular compensatory mechanisms activated by hemorrhage and reduced the blood loss necessary to cause hypotension (10.2 +/- 2.5 mL/kg). Furthermore, anesthesia totally abolished the effect of i.c.v. hypertonic NaCl (10.4 +/- 2.2 mL/kg) and blunted the response to i.v. hypertonic NaCl (15.9 +/- 2.1 mL/kg) seen in conscious animals. The results show that an intact autonomic cardiovascular control is crucial for the effect of i.c.v. hypertonic saline and indicate that i.v. hypertonic saline exerts some of its action through the central nervous system.