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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/H1882    most recent 00092.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Foudi, N. Articles by Bäck, M. PubMed PubMed Citation Articles by Foudi, N. Articles by Bäck, M.

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

Bichat Hospital (¹INSERM U698, ²University of Paris 13 and ³University of Paris 7), Paris Cedex 18, France; and ⁴Department of Cardiology and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

Submitted February 3, 2009 ; accepted in final form September 10, 2009

Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 µmol/l) and indomethacin (1.7 µmol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I₂ but not of prostaglandin E₂, prostaglandin D₂, or thromboxane A₂ in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I₂ release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

atherosclerosis; cyclooxygenase; eicosanoids; prostaglandins; vascular reactivity