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

Circulation. 2001 Aug 14;104(7):820-5. doi: 10.1161/hc3301.092790.

Abstract

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 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.

Methods and results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Arachidonic Acid / pharmacology
  • Aspirin / pharmacology
  • Benzofurans / pharmacology
  • Blood Flow Velocity / drug effects
  • Celecoxib
  • Coronary Circulation / drug effects
  • Coronary Thrombosis / drug therapy*
  • Coronary Thrombosis / physiopathology
  • Coronary Vessels / drug effects*
  • Coronary Vessels / physiopathology
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / adverse effects
  • Cyclooxygenase Inhibitors / pharmacology*
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Epoprostenol / pharmacology
  • Isoenzymes / antagonists & inhibitors*
  • Platelet Aggregation / drug effects
  • Prostaglandin-Endoperoxide Synthases
  • Pyrazoles
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacology
  • Thromboxane-A Synthase / antagonists & inhibitors
  • Time Factors
  • Vasodilation / drug effects
  • Vasomotor System / drug effects*
  • Vasomotor System / physiopathology

Substances

  • Benzofurans
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Pyrazoles
  • Sulfonamides
  • Arachidonic Acid
  • Epoprostenol
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Thromboxane-A Synthase
  • Celecoxib
  • furegrelate
  • Acetylcholine
  • Aspirin