Effects of inhibitors of the activity of cyclo‐oxygenase‐2 on the hypotension and multiple organ dysfunction caused by endotoxin: A comparison with dexamethasone

Publisher Website
Google Scholar
Abstract
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. 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. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6‐keto‐PGF1α (indicator of the induction of COX‐2) and nitrite/nitrate (indicator of the induction of iNOS). 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. 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.