1. Vascular responses to endothelin-1 (ET-1) and noradrenaline (NA) were measured in isolated Krebs'-perfused kidneys of 2 week old streptozotocin-diabetic and non-diabetic rats. 2. Bolus injections of either ET-1 or NA caused dose-dependent increases in perfusion pressure. Responses to ET-1 (10-60 ng/g kidney), but not to NA (0.001-10 micrograms/g kidney), were significantly potentiated in kidneys of diabetic rats compared with non-diabetics. 3. Indomethacin significantly attenuated responses to NA (0.3-10 micrograms/g kidney) in kidneys of both diabetic and non-diabetic rats. 4. Neither indomethacin (1 mumol/L) nor the cyclo-oxygenase/lipoxygenase inhibitor BW755C (1 mumol/L) had any significant effect on the log dose-response curve to ET-1 in either group of kidneys. 5. Perfusion with N-nitro-L-arginine (NOLA; 10 mumol/L) had no effect on basal perfusion pressures, but potentiated responses to ET-1 in both groups of kidneys. However, the difference in responses to ET-1 between kidneys from diabetic and non-diabetic rats remained significant in the presence of NOLA. 6. ET-1 responses were inhibited in Ca(2+)-free Krebs' solution (plus 1 mmol/L EGTA). 7. The results of the present study indicate an increased sensitivity to ET-1 in isolated Krebs'-perfused kidneys of diabetic rats. Responses to ET-1 were unaffected by cyclo-oxygenase and/or lipoxygenase inhibitors, but were potentiated by an endothelium-derived relaxing factor (EDRF) synthesis inhibitor.