Renal arterial infusion of acetylcholine (ACh) (40 micrograms/min) produces a natriuresis, diuresis, and an increase in renal plasma flow (RPF) without a change in glomerular filtration rate (GFR) or renin secretory rate (RSR). The present study was designed to examine the role of prostaglandins in this natriuretic response to ACh. In dogs pretreated with indomethacin (Indo) (5 mg/kg, i.v.), an inhibitor of prostaglandin synthesis, renal arterial infusion of ACh produced an increase and then a decline in urinary flow and sodium excretion accompanied by a progressive fall in GFR and RPF and a progressive increase in RSR. Renal arterial infusion of PGE2 (1.9 micrograms/min) but not PGF2 alpha (1.9 micrograms/min) before and during the infusion of ACh restored the diuretic and natriuretic response to ACh in Indo-treated dogs. Renal arterial infusion of bradykinin (BK) (3 micrograms/min) in Indo-treated dogs produced a diuresis and natriuresis similar to that produced by PGE2; renal arterial infusion of BK, however, did not restore the diuretic and natriuretic response to ACh in Indo-treated dogs. The data suggest that Indo shortens the diuretic and natriuretic response to ACh by inhibiting synthesis of prostaglandins, possibly PGE but not PGF. The data further suggest that PGE2 restores the diuretic and natriuretic response to ACh in Indo-treated dogs through a specific action rather than by its action as a renal vasodilator.