Piretanide [HOE 118; 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoxylbenzoic acid] is a new diuretic with a saluretic effect similar to that of furosemide. The present experiments were undertaken to investigate if transport of piretanide into the tubular lumen determines the diuretic response and what effect piretanide has on the tubuloglomerular feedback control and loop of Henle electrolyte transport. To study the first question, five healthy subjects were investigated. Piretanide, inulin and p-aminohippuric acid were continuously infused. After equilibration, 1 g of probenecid was given which reduced the tubular secretion of piretanide to one-sixth of control level. The reduction in diuresis was 41.4% while it was 59.5, 63.9 and 45.8% for the urinary excretion of chloride, sodium and potassium, respectively. In a second series of experiments in rats a proximal tubular stop-flow pressure response at increased distal delivery of fluid was measured when Ringer's solution, Ringer's solution plus furosemide (10(-4) M) or bumetanide (5 X 10(-5) M) or piretanide (10(-4) M and 5 X 10(-5) M) was added to the tubular perfusion solution. The results indicate that the feedback could be completely blocked by any of these diuretics. The fluid absorption in the loop of Henle was studied in separate experiments and the addition of piretanide (10(-4) M) greatly reduced chloride and absolute fluid absorption from this nephron segment. The present results indicate that tubular secretion of piretanide is important for the diuretic response and that piretanide inhibits the fluid absorption in the loop of Henle and the tubuloglomerular feedback control which would otherwise blunt the diuretic response with a reduction in glomerular filtration rate.