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 isof orm of cyclo-oxygenase, cyclooxygenase-2 (COX-2), and an overproductio n of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysf unction caused by endotoxin is unclear. Dexamethasone prevents the exp ression of COX-2 and exerts beneficial effects in animal models of sho ck. 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 th e circulatory failure and organ dysfunction caused by lipopolysacchari de (LPS, E. coli, 6 mg kg(-1), i.v., n = 11) in the rat. 3 Endotoxaemi a for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-ke to-PGF(1 alpha) (indicator of the induction of COX-2) and nitrite/nitr ate (indicator of the induction of iNOS). 4 Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the h epatocellular and pancreatic injury and the induction of COX-2 and iNO S caused by LPS. In contrast, inhibition of COX-2 activity with SC-586 35 or NS-398 neither attenuated the circulatory failure nor the multip le organ failure caused by endotoxin. 5 Thus. the prevention of the ci rculatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of C OX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or d ysfunction in rats with endotoxaemia.