Effect of endogenously produced leukotrienes and thromboxane on renal vascular resistance in rabbit hydronephrosis

Abstract

Ureteral obstruction in rabbits is characterized by mononuclear cell invasion of the renal cortex and proliferative fibrosis that is associated with exaggerrated prostaglandin synthesis in response to vasoactive and inflammatory cell agonists. In this investigation, we studied the effects of the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) and bradykinin (BK) on eicosanoid synthesis and renal vascular resistance in the ex vivo perfused hydronephrotic kidney (HNK). Administration of fMLP resulted in the dose-dependent synthesis of leukotrienes, thromboxane A2 (TXA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). Peptidoleukotriene synthesis was monitored by specific radioimmunoassay and by guinea pig ileum bioassay and it was then validated by inhibition of the ileal contractile activity with the peptidoleukotriene receptor antagonist FPL-55712. The leukotrienes produced were identified as LTB4, LTC4, LTD4, and LTE4 by comigration with authentic standards on reverse phase high-performance liquid chromatography (RP-HPLC) and by ultraviolet spectroscopy. BK administration stimulated the synthesis of TXA2, PGE2, and PGI2 but not the synthesis of leukotrienes, in contrast to the results with fMLP, suggesting the involvement of different cell types. Administration of fMLP to the HNK also resulted in a renal vasoconstriction that was partially inhibited by FPL-55712 and that was completely inhibited by the thromboxane synthase inhibitor OKY-1581. Consistent with this result, exogenous administration of LTC4 resulted in the synthesis of TXA2 and in a renal vasoconstriction that was inhibited by either FPL-55712 or OKY-1581. These studies provide conclusive evidence that leukotrienes are produced in renal inflammation, that endogenously produced LTC4 can stimulate the synthesis of TXA2, and that LTC4-induced vasoconstriction is mediated by the production of TXA2. The vasoconstrictor effects of endogenously produced leukotrienes and thromboxane suggest a pathophysiologic role for these substances in renal inflammation.