title: Effect of celecoxib on cyclooxygenase-1-mediated prostacyclin synthesis and endothelium-dependent contraction in mouse arteries.
abstract: This study aimed to determine whether a cyclooxygenase-2 (COX-2) inhibitor celecoxib influences endothelium-dependent contraction independent of its action on COX-2 and, if so, the underlying mechanism(s). Abdominal aortas and/or carotid arteries from C57BL/6 mice or those with genetic COX-2 deficiency (COX-2(-/-)) were isolated for functional and/or biochemical analyses. Result showed that following NO synthase inhibition celecoxib not only reduced the contraction evoked by acetylcholine in C57BL/6 abdominal aorta, but also that in COX-2 (-/-) mice showing a comparable magnitude. Notably, the IC(50) of celecoxib obtained in COX-2 (-/-) abdominal aorta was only ~0.364 μM. Also, celecoxib exhibited a similar effect on COX-2 (-/-) carotid arteries. Interestingly, celecoxib was not only found to inhibit the production of the prostacyclin (PGI(2)) metabolite 6-keto-PGF (1α) in COX-2 (-/-) aortas, but also caused a reduction in the contraction evoked by PGI(2), by the α(1)-adrenergic agonist phenylephrine, or by 30 mM K(+)-induced depolarization in COX-2 (-/-) and/or C57BL/6 abdominal aorta. Moreover, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398), another COX-2 inhibitor, also reduced the contraction evoked by acetylcholine or by 30 mM K(+)-induced depolarization in COX-2 (-/-) mice. These results demonstrate explicitly that in mouse arteries celecoxib not only inhibits COX-1-mediated synthesis of PGI(2) and probably some other prostanoids, but also causes a reduction in vessel contractility that is independent of either COX-2 or COX-1, leading to an inhibition of COX-1-mediated endothelium-dependent contraction with an IC(50) value far below that of it considered for COX-1 . Also, our data suggest that such effects of celecoxib could be possibly shared by some other COX-2 inhibitors, such as NS398.
authors.affiliation: Cardiovascular Research Center, Shantou University Medical College, 22 Xin-Ling Road, Shantou 515041, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Luo
authors.forename: Yingzhan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Ningxia
authors.initials: N
authors.lastname: Zhu
authors.forename: Dongyang
authors.initials: D
authors.lastname: Huang
authors.forename: Yingbi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011464:Epoprostenol / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010656:Phenylephrine / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D010656:Phenylephrine; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D000109:Acetylcholine; D007213:Indomethacin