Adult male rats were injected subcutaneously with polyethylene glycol (PEG) solution, which causes hypovolemia by progressive isosmotic leaching of plasma fluid into a local edema. Plasma levels of arginine vasopressin (AVP) were found to increase exponentially in response to induced plasma volume deficits up to 40%. However, plasma AVP was reduced to basal levels when the rats were given either free access to drinking water or intragastric water loads that diluted plasma osmolality by only 3-6% despite continued hypovolemia. Administration of hypertonic NaCl stimulated AVP secretion as well. However, combined PEG and hypertonic NaCl treatments produced plasma AVP levels greater than expected from simple additivity of the independent effects of hypovolemia and osmotic concentration. Oxytocin secretion similarly was stimulated by treatment with either PEG solution or hypertonic NaCl, it was especially pronounced when both treatments were given, and it was inhibited by osmotic dilution despite marked hypovolemia. These effects are analogous to those seen when hypovolemia stimulates water intake but subsequent osmotic dilution inhibits thirst in PEG-treated rats.