benzofurans and Coronary-Thrombosis

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 increasing blood flow to injured tissues, reducing leukocyte adherence, and inhibiting platelet aggregation. We examined the possibility that selective COX-2 inhibition could suppress the protective effects of prostacyclin, resulting in an alteration of the hemostatic balance and vascular tone.. Circumflex coronary artery thrombosis was induced in dogs by vascular electrolytic injury. Orally administered celecoxib (COX-2 inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not alter 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 minutes). Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibition) produced a significant increase in time to vessel occlusion (257.0+/-41.6 minutes). The observed increase in time to occlusion was abolished when celecoxib was administered to animals dosed with HDA-ER (80.7+/-20.6 minutes). The vasomotor effect of endothelium-derived prostacyclin was examined by monitoring coronary flow during intracoronary administration of arachidonic acid or acetylcholine. In celecoxib-treated animals, vasodilation in response to arachidonic acid was reduced significantly compared with controls.. The results indicate important physiological roles for COX-2-derived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased in individuals with underlying inflammatory disorders, including coronary artery disease.

Topics: Acetylcholine; Animals; Arachidonic Acid; Aspirin; Benzofurans; Blood Flow Velocity; Celecoxib; Coronary Circulation; Coronary Thrombosis; Coronary Vessels; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Isoenzymes; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Thromboxane-A Synthase; Time Factors; Vasodilation; Vasomotor System

Topics: Animals; Benzofurans; Coronary Disease; Coronary Thrombosis; Dibenzothiepins; Dogs; Platelet Aggregation; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane-A Synthase