The effect of a single oral dose of 25 mg bemetizide on renal function without and with concomitant administration of the prostaglandin synthesis inhibitor indomethacin was investigated in ten healthy volunteers during sustained water diuresis. Bemetizide induced a significant increase in urinary sodium and chloride excretion from 196 +/- 30 and 163 +/- 28 mumol/min to 690 +/- 54 and 537 +/- 51 mumol/min (P less than 0.01). This effect occurred in the absence of changes in glomerular filtration rate, urinary excretion of phosphate or the delivery of chloride beyond the proximal nephron to the distal tubules (distal delivery) [(CH2O + CCl)/GFR . 100], but was associated with a significant decrease in distal fractional chloride absorption (DFACl) [CH2O/(CH2O + CCl)] from 0.84 +/- 0.02 to 0.63 +/- 0.02 (P less than 0.01). Bemetizide also increased urinary excretion of prostaglandin (PG) E2. Concomitant indomethacin administration significantly suppressed urinary excretion of PGE2 and markedly decreased urinary excretion of sodium and chloride during control and following bemetizide administration. Indomethacin had no effect on glomerular filtration rate, urinary excretion of phosphate, distal delivery or the urinary excretion of bemetizide but significantly increased DFACl both during control and after bemetizide administration. Our results show that bemetizide as a thiazide-diuretic acts in the diluting segments of the nephron. Indomethacin administration induces retention of sodium and chloride and blunts the renal effects of bemetizide via increased absorption in the diluting segments. The interaction of both drugs most likely represents a pharmacodynamic interaction.