Effects of selective cyclooxygenase-2 inhibition on vascular responses andthrombosis in canine coronary arteries

Background-Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a component of the inflammatory response. Prostacyclin, a product of COX -2 in vascular endothelium, has important physiological roles, such as incr easing blood flow to injured tissues, reducing leukocyte adherence, and inh ibiting platelet aggregation. We examined the possibility that selective CO X-2 inhibition could suppress the protective effects of prostacyclin, resul ting in an alteration of the hemostatic balance and vascular tone. Methods and Results-Circumflex coronary artery thrombosis was induced in do gs by vascular electrolytic injury. Orally administered celecoxib (COX-2 in hibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not a lter time to occlusive thrombus formation compared with controls (celecoxib 77.7 +/-7.2 minutes, HDA 72.0 +/- 18.5 minutes, control 93.0 +/- 21.8 minu tes). Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibiti on) produced a significant increase in time to vessel occlusion (257.0 +/- 41.6 minutes). The observed increase in time to occlusion was abolished whe n celecoxib was administered to animals dosed with HDA-ER (80.7 +/- 20.6 mi nutes). The vasomotor effect of endothelium-derived prostacyclin was examin ed by monitoring coronary flow during intracoronary administration of arach idonic acid or acetylcholine. In celecoxib -treated animals, vasodilation i n response to arachidonic acid was reduced significantly compared with cont rols. Conclusions-The results indicate important physiological roles for COX-2-de rived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be inc reased in individuals with underlying inflammatory disorders, including cor onary artery disease.