A method for maintaining chronic severe hypoosmolality in rats is described utilizing subcutaneous infusions of the antidiuretic vasopressin analogue 1-deamino-[8-D-arginine] vasopressin (DDAVP) at rates of 1 or 5 ng/hr via osmotic minipumps in combination with self-ingestion of a concentrated, nutritionally-balanced liquid diet. Using these methods, 97.3% of all rats studied achieved stable levels of severe hyponatremia (plasma [Na+] = 111.6 +/- 0.5 mEq/liter, N = 213), which was sustained for periods of time ranging from two to five weeks. Mortality was low (1.8%) and observable morbidity was not noted over a series of studies encompassing 4,628 rat days of sustained hypoosmolality. Analysis of food intake and body weight revealed no evidence of tissue catabolism at any time with the lower (1 ng/hr) DDAVP infusion rate, and only during the first week with the higher (5 ng/hr) rate. Metabolic balance studies during 13 days of sustained hypoosmolality demonstrated the dilutional nature of the hypoosmolality, and only a limited degree of renal escape from the antidiuretic effects of DDAVP (urine osmolalities 800 to 1200 mOsm/kg H2O). Studies of brain water and electrolyte contents demonstrated complete normalization of brain volume after 14 to 28 days of sustained hypoosmolality, the major part of which (70%) could be accounted for by loss of brain electrolytes. Both natriuresis and kaliuresis occurred during the first five days of hypoosmolality, and were of sufficient magnitude to suggest some degree of adaptation of other body fluid compartments via electrolyte losses as well. These results indicate that rats have substantial capacity to tolerate prolonged severe hypoosmolality with little morbidity and mortality as long as proper attention is paid to their nutritional requirements, and provide further evidence that brain volume regulation likely represents the major adaptive mechanism that allows survival despite sustained hypoosmolality.