The effects of L-NGnitroarginine (LNNA), a nitric oxide synthase inhibitor, and ibuprofen, a cyclooxygenase inhibitor, on the renal actions induced by endothelin (ET)-3 were studied in anesthetized dogs. Continuous infusion of ET-3 in a dose of 5 ng/kg/min for 25 min increased both renal blood flow (RBF) and urine flow rate. In dogs given LNNA (75 micrograms/kg/min for 25 min), the RBF decreased after intrarenal administration of ET-3 (5 ng/kg/min). Glomerular filtration rate (GFR) was unchanged throughout the infusion of ET-3, in dogs treated with and without LNNA. In dogs given ibuprofen (12.5 mg/kg i.v.), an initial increase in RBF was evident after initiating infusion of the peptide, to be followed by a gradual reduction in RBF, GFR decreased significantly with ET-3, whereas the degree of reduction in RBF was the same in dogs treated with LNNA. Thus, ET-3 acts as a vasodilatory and diuretic peptide in the dog kidney. Presumably ET-3 enhances the release of nitric oxide and prostaglandins and then renal vasodilation occurs. Although the enhanced production of prostaglandins by ET-3 may be responsible for maintaining GFR, it is not linked to the initial phase of renal vasodilation.