A B S T R A C T In order to determine whether or not antidiuretic hormone (ADH) is essential to the inhibition of an acute water diuresis in adrenal insufficiency, the response to oral water loads was tested in rats with hereditary hypothalamic diabetes insipidus (DI) which lack ADH. It was found that 60 min after water loads of 3 or 5% of body weight urine flow was significantly lower and urine osmolality significantly higher in adrenalectomized DI rats than in the same DI rats before removal of their adrenal glands.The efficacy of gluco-and mineralocorticoids in reversing the inhibition was then determined in the same adrenalectomized DI rats. Prednisolone alone, administered either acutely or chronically, restored the response in urine flow to that seen in the same rats before adrenalectomy, but failed to correct the defect in urinary dilution. Aldosterone when given alone tended to correct the diluting ability but not the response in urine flow. When these two adrenal cortical hormones were given simultaneously, both the urine flow and urine osmolality were nearly identical to what they had been in the same DI rats before adrenalectomy. These studies strongly suggest (a) that ADH is not essential to the inhibition of an acute water diuresis in adrenal insufficiency, although it may abet the inhibition in individuals without diabetes insipidus, which can elaborate ADH; and (b) that both gluco-and mineralocorticoids are required in adrenal insufficiency in order to fully restore the water diuresis as judged by the dual criteria of urine flow and urine osmolality. INTRODUCTIONThe mechanism by which an acute water diuresis is inhibited in adrenal insufficiency has been the subject of intensive investigation and debate. (For a list of references, see reference 1.) Although changes such as decreased extracellular fluid volume or decreased glomerular filtration rate (GFR) may contribute to the inhibition, it seems clear that these are not the only, or even the major, factors involved. The main current controversy centers about the role of the antidiuretic hormone (vasopressin or ADH). One view states that in adrenal insufficiency water diuresis is inhibited by sustained high blood concentrations of ADH because in the absence of adrenal corticoids, secretion of ADH from the posterior pituitary gland cannot be shut off (2). Proponents of the second view contend that ADH has little to do with the inhibited water diuresis, but rather, that the adrenal steroids alter the water permeability of the distal renal tubules and collecting ducts (3). Both views have been supported by results of bioassays, the first showing sustained, high concentration of ADH in the blood of patients with adrenal insufficiency even after an acute water load (2), the second showing undetectable blood levels of ADH under similar circumstances (3).