Endothelin has been implicated in the pathogenesis of acute renal failure associated with radiocontrast media. The current study was designed to determine the effect of endothelin receptor blockade in a model of radiocontrast-induced nephropathy. Inhibition of prostanoids and nitric oxide with indomethacin and L-nitroarginine methyl ester (L-NAME) predisposes rats to the nephrotoxic effects of radiocontrast media and, therefore, has been proposed as a clinically relevant model. Separate groups of conscious rats were given the ETA receptor antagonist, A-127722 (3, 10, or 30 mg/kg), or water (1 mL/kg) by oral gavage. All rats were then given indomethacin (10 mg/kg), L-NAME (10 mg/kg), and the contrast agent, diatrizoate (6 mL/kg), by intravenous injection at 15-min intervals. Urine was collected for the subsequent 24 h by placing rats in metabolism cages. When indomethacin, L-NAME, and diatrizoate were administered without A-127722, rats displayed typical signs of renal failure; protein excretion was increased from a baseline of 13 +/- 2 to 33 +/- 8 mg/day (p < 0.05) and plasma creatinine increased from 0.52 +/- 0.01 to 0.62 +/- 0.04 mg/dL (p < 0.05). ETA receptor blockade prevented the rise in protein excretion and plasma creatinine in a dose-dependent manner. In separate series of clearance experiments, A-127722 completely inhibited the renal effects of exogenous ET-1. These results suggest that endothelin plays a role in the hemodynamic events in this model and that ETA receptor antagonists should be investigated as potential therapeutic agents for radiocontrast-induced nephropathy.