To determine whether extracerebral osmoreceptors contribute to vasopressin release when exposed to blood osmolality changes of about 1%, we administered hypertonic saline solution to five conscious dogs through catheters chronically implanted into the inferior vena cava, the portal vein, the artery to a sole remaining kidney, and the common carotid arteries. Each infusion was given on a different day at a rate of 0.2 ml/min, which provided about 25 mumol NaCl/kg BW X min. The changes in plasma sodium concentration and plasma osmolality measured during these infusions were similar with all four routes of administration and significantly different from those after iv infusion of isotonic saline solution. Plasma vasopressin concentration, measured by RIA, increased more rapidly after intracarotid infusions than with any other route. We found no evidence that renal or portal/hepatic osmoreceptors contributed to vasopressin release under the conditions of our study.