Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure

Bolus i.v. administration of 100 μg/kg of E. Coli lipopolysaccharide endotoxin (LPS) to adult male Munich-Wistar rats (N = 18) resulted in a progressive fall in RBF and GFR from 6.9 ± 0.2 SE and 1.1 ± 0.05 ml/min to minimal values at 50 minutes of 3.8 ± 0.4 and 0.32 ± 0.08 (P <0.05), respectively, without a fall in mean arterial pressure. At 50 minutes, renal cortical generation rates of PGE₂ (1075 ± 108 pg/mg tissue), 6 keto PGF(1α) (221 ± 41 pg/mg), and TxB₂ (106 ± 12 pg/mg) were significantly higher than those of vehicle-treated control rats (N = 10, PGE₂ = 466 ± 107, 6 keto PGF(1α) = 94 ± 3, and TxB₂ = 35 ± 3 pg/mg), and morphologic examination revealed normal histology with notable absence of leukocytes and platelets. Pretreatment of a third group of nine rats with TxA₂ synthetase inhibitor UK-37.248 (dazoxiben, 10 mg/kg) selectively abolished the LPS-induced rise in TxB₂ (29 ± 3 pg/mg), but not PGE₂ (837 ± 62 pg/mg) or 6 keto PGF(1α) (179 ± 5 pg/mg), prevented the fall in RBF at 50 minutes (6.3 ± 0.4 ml/min), and allowed for significant preservation of GFR (0.67 ± 0.08 ml/min). In addition, antagonism of endogenously produced LTs with the putative receptor antagonist FPL55712 (N = 10, 500 μg/kg/min x 40 min), while not preventing the LPS-induced rise in TxB₂ generation rate (97 ± pg/mg); significantly ameliorated the fall in RBF at 50 minutes (5.9 ± 0.5 ml/min), whereas GFR was depressed (0.46 ± 0.13 ml/min), but recovered to 0.57 ± 0.08 ml/min at 70 min post-LPS (P <0.05 vs. LPS alone). These observations point to major roles for TxA₂ and sulfidopeptide LTs in mediating the renal functional impairment of experimental endotoxemia.