Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin-1

Br J Pharmacol. 1991 Jul;103(3):1663-8. doi: 10.1111/j.1476-5381.1991.tb09844.x.

Abstract

1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF 1 alpha and 2,3-dinor-6-oxo-PGF 1 alpha (products of PGI2) at 24 h. 3. Interleukin-1 (IL-1 beta; 5 micrograms) alone caused an increase in PGI2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4. Pretreatment of rats with IL-1 beta before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1 beta alone. 5. The cyclo-oxygenase inhibitor, ibuprofen (10 mgkg-1 i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/IL-1 beta. 6. We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Ketoprostaglandin F1 alpha / analogs & derivatives
  • 6-Ketoprostaglandin F1 alpha / urine
  • Animals
  • Creatinine / metabolism
  • Cyclooxygenase Inhibitors / pharmacology
  • Epoprostenol / urine*
  • Ibuprofen / pharmacology
  • In Vitro Techniques
  • Interleukin-1 / pharmacology*
  • Kidney Glomerulus / metabolism
  • Male
  • Nephritis / chemically induced
  • Nephritis / urine*
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Rats
  • Rats, Inbred Strains
  • Thromboxane B2 / analogs & derivatives
  • Thromboxane B2 / metabolism
  • Thromboxane B2 / urine
  • Thromboxanes / urine*

Substances

  • Cyclooxygenase Inhibitors
  • Interleukin-1
  • Thromboxanes
  • Thromboxane B2
  • 6-Ketoprostaglandin F1 alpha
  • 2,3-dinor-thromboxane B2
  • 2,3-dinor-6-ketoprostaglandin F1alpha
  • Creatinine
  • Epoprostenol
  • Ibuprofen