Digoxin acts at central neural (CNS) as well as peripheral sites after intravenous administration. In contrast, the analog, 3-beta-O(4-amino-4,6-dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222), cannot cross the blood-brain barrier so it acts only at sites outside the CNS. The effects of these two agents on plasma antidiuretic hormone activity (ADH) were investigated in conscious dogs. Despite previous evidence that digoxin produces reflex decreases in sympathetic nerve activity by activating ventricular receptors with vagal afferents, no decreases in ADH were detected when either digoxin (25 and 50 micrograms/kg) or ASI-222 (38.5 micrograms/kg) were administered intravenously even with preexisting high levels of plasma ADH. In contrast, both digoxin (50 micrograms/kg) and ASI-222 (38.5 micrograms/kg) resulted in increased ADH levels, but only in association with emesis and behavioral changes suggestive of nausea. Cerebroventricular (IVT) injections of digoxin were given, starting with a dose of 0.1 microgram, that were intended to produce a comparable cerebrospinal fluid (CSF) concentration to that associated with the 50 micrograms/kg intravenous dose. Only the highest dose of digoxin, 1 micrograms, but not 0.1 and 0.3 micrograms, produced increases in ADH and emesis when given into the lateral cerebral ventricle. This is further evidence that a site accessible to blood but not to CSF was involved. These results suggest that digoxin and ASI-222 may activate pathways in the area postrema and produce increases in ADH as well as emesis.