INHIBITION BY NITRIC OXIDE-RELEASING COMPOUNDS OF PROSTACYCLIN PRODUCTION IN HUMAN ENDOTHELIAL-CELLS

1 The effects of two chemically unrelated nitric oxide (NO)-releasing compounds were studied on prostacyclin production in lipopolysaccharid e (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). Th e cells expressed cyclooxygenase-2 (COX-2) protein and produced prosta cyclin by NS-398-sensitive manner suggesting that prostacyclin product ion derives principally by COX-2 pathway. 2 A novel NO-releasing oxatr iazole derivative GEA 3175 (1-30 mu M) inhibited LPS-induced productio n of prostacyclin in HUVECs in a dose-dependent manner being more pote nt than the earlier known NO-donor S-nitroso-N-acetylpenicillamine (SN AP). 3 The effects of the two NO-donors on prostacyclin synthesis were reversed when red blood cells were added into the culture indicating that the effects are due to NO released from the compounds. 4 Addition of exogenous arachidonic acid into the culture did not alter the inhi bitory action of NO-donors suggesting that phospholipases are not the target of action of NO. 5 The NO-donors did not inhibit prostacyclin p roduction in the presence of a selective COX-2 inhibitor NS-398. These data suggest that NO affects COX-2 pathway rather than has an overall effect on cyclooxygenases. 6 NO-releasing compounds did not alter the level of COX-2 protein expression in LPS-treated HUVECs as measured b y Western blot analysis. 7 The results suggest that NO-donors inhibit the activity of COX-2 in human endothelial cells. A. link between NO a nd the regulation of eicosanoid synthesis could represent an important mechanism in controlling vascular and inflammatory responses in patho physiological states and during treatment with nitrovasodilators.