Atrial Natriuretic Factor (ANF) has been demonstrated within the central nervous system (CNS), where it has been implicated in the regulation of blood pressure, fluid and electrolyte balance. To explore the effect of acute plasma vol expansion on the activation of CNS ANF, changes in ANF levels of CSF drawn from the cisterna magna of anesthetized sheep were measured. Intravenous infusions of Dextran (10 ml/kg body wt, n = 7) or control (total vol 7.5 ml Dextran, n = 7) were administered over 30 min. Compared to control experiments, plasma vol expansion resulted in a 3-fold increase of central venous pressure (P = 0.002), a 25% increase in mean arterial pressure (P = 0.011), and a 20% reduction in packed red cell volume (P = 0.024). Accompanying these hemodynamic changes, plasma ANF concentrations doubled (17.0 +/- 3.0-41.0 +/- 7.8 pmol/liter at 60 min vs. 20.0 +/- 4.7-19.3 +/- 3.6 pmol/liter in controls) and remained elevated for 4 h, whereas CSF ANF concentrations showed a transient 3-fold increase (2.1 +/- 0.3-6.6 +/- 1.9 pmol/liter at 120 min vs. 2.5 +/- 0.5-3.8 +/- 0.7 pmol/liter in controls). The maximum increments of both plasma and CSF ANF were statistically significant (P = 0.002 and 0.03, respectively). Basal CSF levels were approximately 1/10 those in plasma, and no correlation was seen in either basal plasma and CSF levels, or the maximum increments of plasma and CSF ANF concentrations. In vol-expanded sheep, plasma cyclic GMP concentrations tended to increase, although not significantly different from controls, while CSF cyclic GMP was similar to controls throughout the experiments. The entry of ANF to cisterna magna CSF was studied in five additional anesthetized sheep. Infusion iv of ileu rat ANP (50 ng/kg.min over 60 min) raised plasma ANF levels 30-fold, but CSF ANF concentrations did not change. These experiments show that plasma vol expansion in sheep, in addition to stimulating cardiac ANF secretion, induces an increase in CSF ANF, which cannot be accounted for by transfer of ANF from blood into CSF.