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

K. F. Badr, V. E. Kelley, H. G. Renneke, B. M. Brenner

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)474-480
Number of pages7
JournalKidney International
Volume30
Issue number4
Publication statusPublished - 1986
Externally publishedYes

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ASJC Scopus subject areas

  • Nephrology

Cite this

Badr, K. F., Kelley, V. E., Renneke, H. G., & Brenner, B. M. (1986). Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure. Kidney International, 30(4), 474-480.