Vehicle or amphotericin B (AmB) (0.02 mg/kg per min) were infused into the left renal artery in 3 groups of euvolemic male rats: Group 1 (n=6) received vehicle for 90 min (time control); Group 2 (n=5) received vehicle (30 min) followed by AmB for 30 min, followed by 30 min recovery; and Group 3 (n=5) as in Group 2, but rats were pretreated with the cyclooxygenase (CO) inhibitor, ibuprofen (20 mg/kg). No changes in renal plasma flow (RPF) or glomerular filtration rate (GFR) were noted in Group 1. AmB infusion resulted in an immediate and progressive reduction in RPF and GFR from baseline values of 4.13+or-0.22 and 0.83+or-0.07 ml/min to minimal values at 30 min of 2.23+or-0.52 and 0.44+or-0.08 ml/min. No effect was noted on systemic arterial pressure. Upon stopping AmB, partial recovery was observed in both RPF and GFR to 3.56+or-0.43 and 0.71+or-0.05 ml/min, respectively. CO inhibition in Group 3 significantly ameliorated the falls and improved the recoveries of RPF and GFR in response to AmB. These parameters fell from 3.63+or-0.26 and 0.78+or-0.05 ml/min to 2.83+or-0.16 and 0.57+or-0.03 ml/min at 30 min, and recovered to 3.78+or-0.34 and 0.70+or-0.08 ml/min, respectively. A fourth group of 5 animals were infused with AmB as in Group 2, but in the presence of the TxA2 receptor antagonist SQ 29548 (1 mg/kg bolus, then 1 mg/kg hourly, intravenously). In these rats, the first 15 min of AmB infusion were associated with mild increases in RPF and GFR from baseline values of 4.22+or-0.33 and 0.76+or-0.03 ml/min to 4.37+or-0.35 and 0.80+or-0.05 ml/min, followed over the subsequent 15 min by insignificant falls to 3.31+or-0.32 and 0.61+or-0.03 ml/min. Termination of AmB infusion resulted in complete recovery of RPF and GFR to 4.00+or-0.63 and 0.75+or-0.1 ml/min. It is concluded that the renal arteriolar constrictor and GFR-depressant actions of AmB are likely mediated, in part, but the local release of the potent vasoconstrictor, TxA2. It is suggested that antagonism of TxA2 actions may provide a useful tool for limiting AmB nephrotoxicity.