1. The mechanism of the antidiuretic effect of hydrochlorothiazide in diabetes insipidus was studied in anaesthetized Brattleboro rats with the hereditary hypothalamic form of the disease.
2. The antidiuresis caused by acute administration of hydrochlorothiazide followed an increase in sodium excretion and was associated with a significant fall in the plasma sodium concentration. There were concomitant falls in effective renal plasma flow and glomerular filtration rate.
3. When sodium depletion was prevented by adjusting the infusion of sodium chloride, the falls in plasma sodium concentration, effective renal plasma flow and glomerular filtration rate were abolished. Under these circumstances there was an increase in urine volume, which suggests that hydrochlorothiazide may inhibit fractional fluid reabsorption in the proximal convoluted tubule.
4. The results indicate that the antidiuresis caused by hydrochlorothiazide in diabetes insipidus results, at least in part, from falls in effective renal plasma flow and glomerular filtration rate. These in turn seem to be entirely secondary to the drug-induced sodium depletion.