Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 24, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn287
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Selective COX-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation
1 INSERM U698: Haemostasis, Bio-engineering and Cardiovascular Remodeling, Paris 75018, France
2 CHU X. Bichat, Paris 75018, France
3 Paris XIII University, Villetaneuse 93430, France
Corresponding author: Dr Xavier Norel, INSERM U698, CHU X. Bichat, 46, rue Henri Huchard, 75018 Paris, France, Telephone number: +33140257529, Fax number: +33140258602, Email: xnorel{at}hotmail.com
Aims: The use of cyclooxygenase-2 (COX-2) inhibitors has been reported to be associated with detrimental vascular events. The aim of our study was to evaluate the role of COX-2 activity in the control of human vascular tone under inflammatory conditions.
Methods: Using organ bath experiments, the contraction induced by norepinephrine, U46619 [GenBank] , acetylcholine and KCl was performed on isolated human internal mammary arteries cultured in the presence or absence of both interleukin1β and lipopolysaccharide with or without endothelium. Under these conditions the cyclooxygenase isoforms were detected by immunohistochemistry and Western blot, and the prostaglandins and thromboxane released were measured using an enzyme immunoassay kit.
Results: A significant decrease of the maximal effect induced by norepinephrine but not by other stimuli was observed in the interleukin1β- and lipopolysaccharide-treated preparations after 6 and 24 hours of culture (19±6% and 25±4%, respectively), an effect that was endothelium independent. Under this inflammatory condition, the COX-2 inhibitors DFU (1 µmol/L), DuP-697 (0.5 µmol/L) and Etoricoxib (1 µmol/L) markedly restored and increased the vascular reactivity to norepinephrine. These alterations were not observed with SC-560 (1 µmol/L), a selective COX-1 inhibitor. In addition, the COX-1 isoform was always detected and the COX-2 isoform was only found in human internal mammary arteries exposed for 6 or 24 hours under inflammatory conditions. The COX-2 induction was accompanied by an increase of prostaglandin E2 and prostaglandin I2 release in the culture medium (
2.5 fold) but not with an increase in thromboxane A2 release.
Conclusion: These observations suggest that the inhibition of COX-2 directly potentiates the human vascular tone induced by norepinephrine under inflammatory conditions.
Time for primary review: 17 Days
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