COX-2 is involved in inflammation and ischemic cardiovascular disease. As NO regulates COX activity in various cells, we investigated the effect of NO-donors and the novel NO-aspirin NCX-4016 on human monocyte COX-2. Whole blood was incubated with LPS and PGE(2) was measured in plasma as an index of monocyte COX-2 activity. Serum TxB(2) was assessed as an index of platelet COX-1 activity. SNP, DetaNONOate, and NO-aspirin inhibited dose-dependently PGE2 production while aspirin was ineffective. The guanylyl-cyclase inhibitor ODQ partially reversed the suppression of COX-2 activity by NO-aspirin, demonstrating a role of cGMP increase. NCX-4016 and aspirin inhibited platelet COX-1 comparably while NO-donors were ineffective. COX-2 expression was not affected by NO-donors or NO-aspirin while aspirin or the selective COX-2-inhibitor DUP697 increased it. In conclusion, Nitroaspirin inhibits monocyte COX-2 activity by a cGMP-dependent mechanism. This might represent an advantage over aspirin, given the possible detrimental role of COX-2 in cardiovascular disease. (C) 2003 Elsevier Inc. All rights reserved.