Eicosanoid synthesis inhibition and renal allograft function during acute rejection

The effects of the dual cyclooxygenase-lipoxygenase inhibitor 3-amino-l-(m[trifluoromethyl]phenyl)-2-pyr- azoline (BW755C) (10 mg/kg, p.o., b.i.d.) on renal blood flow, glomerular filtration rate (GFR), and eicosanoid production were examined in anesthetized dogs that had undergone unilateral renal allotransplantation. Reject-ing renal allograft blood flow significantly declined over a 5-day period compared to the nonrejecting native kid-ney. In animals treated with BW755C, renal allograft blood flow was maintained over the postoperative 5-day period at levels comparable to blood flow to the native kidneys. While GFR and urine flow progressively declined in the rejecting kidney, treatment with BW755C prevented the fall in GFR and even augmented urine flow. Allograft renal cortical production or thromboxane B2 (TXB2) and leukotriene B4 (LTB4) in animals treated with BW755C was not significantly different than production by the native contralateral kidneys. Furthermore, BW755C reduced cellular infiltration and tissue damage in allografts compared to nontreated renal allografts. The selective cyclooxygenase inhibitor, indomethacin (5 mg/kg, p.o., b.i.d.) exerted no effect on renal allograft GFR or urine output but reduced allograft blood flow after 4 days compared to nontreated allografts. In conclusion, inhibition of arachidonate cyclooxygenase and lipoxygenase metabolism improves renal allograft function and reduces tissue damage while selective inhibition of the cyclooxygenase pathway does not improve renal allograft function. These data indicate that products of arachidonate-lipoxygenase metabolism potentiate the loss of renal function and tissue destruction associated with renal allograft rejection.