The cyclooxygenase-2 selective inhibitor, etodolac, but not aspirin reduces neovascularization in a murine ischemic hind limb model.

Abstract

Cyclooxygenase inhibitors are often prescribed to relieve severe ischemic leg pain in critical ischemic limb patients. Prescription of high doses of aspirin and selective cyclooxygenase-2 inhibitors is reported to increase cardiovascular events through suppression of the vasodilative prostanoid prostaglandin I(2) in endothelium. Here, we evaluated the influence of aspirin and etodolac, a selective cyclooxygenase-2 inhibitor, on neovascularization using a murine ischemia hind limb model. C57BL/6J mice were treated with aspirin or etodolac for twenty-eight days after induction of ischemia. We exploited a concentration of the agents that suppressed cyclooxygenase activity efficiently, especially in prostaglandin I(2) production. Recovery of limb blood perfusion and capillary density in ischemic limbs was significantly suppressed by etodolac treatment when compared to the aspirin treated group and untreated group. Production of 6-keto prostaglandin F(1alpha) and prostaglandin E(2) was lower in the aspirin treated group when compared with the etodolac-treated group. Also, these concentrations were lower in both treatment groups compared with the untreated group. Immunohistochemical analysis suggested cyclooxygenase-2 was expressed in endothelium but not in inflammatory cells in ischemic tissue from the acute to chronic phase. Cyclooxygenase-1 was expressed strongly in inflammatory cells in the acute phase. Furthermore, bone marrow-derived mononuclear cell transplantation improved neovascularization, whereas aspirin and etodolac did not inhibit these effects. Production of arachidonic acid metabolites by transplanted cells was independent of the improvement of neovascularization. In conclusion, cyclooxygenase-2 inhibition reduces ischemia-induced neovascularization.

• Authors: Kohei Tanaka, Yasutaka Yamamoto, Shunsuke Tsujimoto, Naonori Uozumi, Yoshihiro Kita, Akio Yoshida, Takao Shimizu, Ichiro Hisatome
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 627 Issue 1-3 Pg. 223-8 (Feb 10 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19879866 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2009 Elsevier B.V. All rights reserved.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Eicosanoids
• Etodolac
• Cyclooxygenase 1
• Cyclooxygenase 2
• Group IV Phospholipases A2
• Aspirin

Topics

• Animals
• Aspirin (pharmacology)
• Bone Marrow Cells (cytology)
• Cell Transplantation
• Cyclooxygenase 1 (metabolism)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Disease Models, Animal
• Eicosanoids (biosynthesis, blood)
• Etodolac (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Group IV Phospholipases A2 (metabolism)
• Hindlimb (blood supply, metabolism, pathology)
• Ischemia (blood, enzymology, metabolism, physiopathology)
• Leukocytes, Mononuclear (transplantation)
• Male
• Mice
• Neovascularization, Physiologic (drug effects)
• Regional Blood Flow (drug effects)