Effects of inhibitors of the activity of cyclo-oxygenase-2 on the hypotension and multiple organ dysfunction caused by endotoxin: a comparison with dexamethasone.
1. Endotoxaemia is associated with the expression of the inducible isoform of cyclo-oxygenase, cyclo-oxygenase-2 (COX-2), and an overproduction of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysfunction caused by endotoxin is unclear. Dexamethasone prevents the expression of COX-2 and exerts beneficial effects in animal models of shock. 2. Here we compare the effects of two inhibitors of COX-2 activity, namely NS-398 (5 mg kg(-1), i.p., n=7) and SC-58635 (3 mg kg(-1), i.p., n=9) with those of dexamethasone (3 mg kg(-1), i.p., n=9) on the circulatory failure and organ dysfunction caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1), i.v., n=11) in the rat. 3. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF1alpha (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS). 4. Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the hepatocellular and pancreatic injury and the induction of COX-2 and iNOS caused by LPS. In contrast, inhibition of COX-2 activity with SC-58635 or NS-398 neither attenuated the circulatory failure nor the multiple organ failure caused by endotoxin. 5. Thus, the prevention of the circulatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of COX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or dysfunction in rats with endotoxaemia.
Leach
M
M
The William Harvey Research Institute, St Bartholomew's and The Royal London School of Medicine and Dentistry.
Hamilton
L C
LC
Olbrich
A
A
Wray
G M
GM
Thiemermann
C
C
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D019446:Endotoxemia / Q000503:physiopathology; D004731:Endotoxins / Q000633:toxicity*; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D007527:Isoenzymes; D009566:Nitrates; D009573:Nitrites; D009578:Nitrobenzenes; D011720:Pyrazoles; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib