Aceylation of
cyclooxygenase (COX)-2 by
aspirin can trigger the formation of 15(R)-epilipoxin A4, or
aspirin-triggered
lipoxin (ATL). ATL exerts protective effects in the stomach. Selective
COX-2 inhibitors block ATL synthesis and exacerbate
aspirin-induced gastric damage.
Nitric oxide-releasing aspirins, including
NCX-4016, have antiplatelet effects similar to
aspirin but do not cause gastric damage. In the present study, we examined whether or not
NCX-4016 triggers ATL synthesis and/or upregulates gastric COX-2 expression and the effects of coadministration of
NCX-4016 with a selective
COX-2 inhibitor on gastric mucosal injury and
inflammation. Rats were given
aspirin or
NCX-4016 orally and either vehicle or a selective
COX-2 inhibitor (
celecoxib) intraperitoneally. Gastric damage was blindly scored, and granulocyte infiltration into gastric tissue was monitored through measurement of
myeloperoxidase activity. Gastric PG and ATL synthesis was measured as was COX-2 expression. Whereas
celecoxib inhibited gastric ATL synthesis and increased the severity of
aspirin-induced gastric damage and
inflammation, coadministration of
celecoxib and
NCX-4016 did not result in damage or
inflammation.
NCX-4016 did not upregulate gastric COX-2 expression nor did it trigger ATL synthesis (in contrast to
aspirin). Daily administration of
aspirin for 5 days resulted in significantly less gastric damage than that seen with a single dose, as well as augmented ATL synthesis.
Celecoxib reversed this effect. In contrast, repeated administration of
NCX-4016 failed to cause gastric damage, whether given alone or with
celecoxib. These studies support the notion that
NCX-4016 may be an attractive alternative to
aspirin for indications such as cardioprotection, including in individuals also taking selective
COX-2 inhibitors.