1. Prostaglandins may play a role in the natriuresis seen after acute circulatory challenges. To assess this role in head-out water immersion, we compared, in clearance studies, the effects of acute (24 h) and chronic (7 days) administration of indomethacin, an inhibitor of prostaglandin synthesis, on the renal response to head-out water immersion in six healthy subjects on a 200 mmol of sodium/day diet and on a 40 mmol of sodium/day diet. 2. Indomethacin caused a similar degree of sodium retention on each of these two diets. 3. During the 40 mmol of sodium/day diet, acute administration of indomethacin decreased sodium excretion before, as well as during, head-out water immersion; however, the relative increase caused by head-out water immersion was normal. After chronic administration of indomethacin, both baseline sodium excretion and the natriuresis induced by head-out water immersion were similar to those in control studies. 4. During the 200 mmol of sodium/day diet, indomethacin had no effect on baseline sodium excretion, nor on the natriuretic effect of head-out water immersion. 5. Head-out water immersion decreased tubular lithium reabsorption and increased diluting segment delivery. Despite opposite effects of indomethacin on these parameters, indomethacin did not prevent the tubular effects of head-out water immersion on either diet. However, indomethacin did prevent the marked increase in estimated renal plasma flow and the fall in filtration fraction that were observed during head-out water immersion in the absence of indomethacin (control). 6. Head-out water immersion was not associated with an increase in urinary excretion of prostaglandins.(ABSTRACT TRUNCATED AT 250 WORDS)