Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin-1.
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.
Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London.
P S
PS
Ward
R W
RW
Fuller
J M
JM
Ritter
S J
SJ
Cashman
A J
AJ
Rees
C T
CT
Dollery
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000652:urine*; D007052:Ibuprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D009393:Nephritis / Q000139:chemically induced / Q000652:urine*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D013931:Thromboxanes / Q000652:urine*
D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D013931:Thromboxanes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028965:2,3-dinor-thromboxane B2; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; D003404:Creatinine; D011464:Epoprostenol; D007052:Ibuprofen