Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation.

Endothelial cyclooxygenase-1-derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors.

Synthesis and Preliminary Evaluation of N-Oxide Derivatives for the Prevention of Atherothrombotic Events.

Thrombosis is the main outcome of many cardiovascular diseases. Current treatments to prevent thrombotic events involve the long-term use of antiplatelet drugs. However, this therapy has several limitations, thereby justifying the development of new drugs. A series of N-oxide derivatives (furoxan and benzofuroxan) were synthesized and characterized as potential antiplatelet/antithrombotic compounds. All compounds (3a,b, 4a,b, 8a,b, 9a,b, 13a,b and 14a,b) inhibited platelet aggregation induced by adenosine-5-diphosphate, collagen, and arachidonic acid. All compounds protected mice from pulmonary thromboembolism induced by a mixture of collagen and epinephrine; however, benzofuroxan derivatives (13a,b and 14a,b) were the most active compounds, reducing thromboembolic events by up to 80%. N-oxide derivative 14a did not induce genotoxicity in vivo. In conclusion, 14a has emerged as a new antiplatelet/antithrombotic prototype useful for the prevention of atherothrombotic events.

Pharmacological evaluation and preparation of nonsteroidal anti-inflammatory drugs containing an N-acyl hydrazone subunit.

A series of anti-inflammatory derivatives containing an N-acyl hydrazone subunit (4a-e) were synthesized and characterized. Docking studies were performed that suggest that compounds 4a-e bind to cyclooxygenase (COX)-1 and COX-2 isoforms, but with higher affinity for COX-2. The compounds display similar anti-inflammatory activities in vivo, although compound 4c is the most effective compound for inhibiting rat paw edema, with a reduction in the extent of inflammation of 35.9% and 52.8% at 2 and 4 h, respectively. The anti-inflammatory activity of N-acyl hydrazone derivatives was inferior to their respective parent drugs, except for compound 4c after 5 h. Ulcerogenic studies revealed that compounds 4a-e are less gastrotoxic than the respective parent drug. Compounds 4b-e demonstrated mucosal damage comparable to celecoxib. The in vivo analgesic activities of the compounds are higher than the respective parent drug for compounds 4a-b and 4d-e. Compound 4a was more active than dipyrone in reducing acetic-acid-induced abdominal constrictions. Our results indicate that compounds 4a-e are anti-inflammatory and analgesic compounds with reduced gastrotoxicity compared to their respective parent non-steroidal anti-inflammatory drugs.