Effect of celecoxib on cyclooxygenase-1-mediated prostacyclin synthesis and endothelium-dependent contraction in mouse arteries
Effect of celecoxib on cyclooxygenase-1-mediated prostacyclin synthesis and endothelium-dependent contraction in mouse arteries
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塞来昔布对环加氧酶 1 介导的前列环素合成和小鼠动脉内皮依赖性收缩的影响
DOI：
10.1016/j.ejphar.2012.10.040
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发表时间：
2013-01-05
影响因子：
5
通讯作者：
Zhou, Yingbi
中科院分区：
文献类型：
--
作者：
Liu, Bin;Luo, Wenhong;Zhou, Yingbi
本研究旨在确定环氧化酶-2（考克斯-2）抑制剂塞来昔布是否影响内皮依赖性收缩，而不依赖于其对考克斯-2的作用，如果是，则确定其潜在机制。分离来自C57 BL/6小鼠或具有遗传性考克斯-2缺陷（考克斯-2（-/-））的小鼠的腹主动脉和/或颈动脉用于功能和/或生化分析。结果表明，塞来昔布抑制NO合成酶后，不仅能抑制乙酰胆碱引起的C57 BL/6小鼠腹主动脉收缩，而且对考克斯-2（-/-）小鼠的收缩作用也有明显的抑制作用。值得注意的是，在考克斯-2（-/-）腹主动脉中获得的塞来昔布的IC 50仅与0.364 μ M相似。此外，塞来昔布对考克斯-2（-/-）颈动脉也表现出类似的作用。有趣的是，塞来昔布不仅能抑制考克斯-2（-/-）腹主动脉中前列环素（PGI（2））代谢产物6-酮-PGF（1 α）的产生，而且还能减少PGI（2）、α（1）-肾上腺素能激动剂苯肾上腺素或30 mM K+诱导的考克斯-2（-/-）和/或C57 BL/6腹主动脉去极化引起的收缩。此外，另一种考克斯-2抑制剂N-[2-（环己氧基）-4-硝基苯基]-甲磺酰胺（NS 398）也可减少乙酰胆碱或30 mM K+诱导的考克斯-2（-/-）小鼠去极化引起的收缩。这些结果明确表明，在小鼠动脉中，塞来昔布不仅抑制考克斯-1介导的PGI（2）和可能的一些其他前列腺素类化合物的合成，而且还导致不依赖于考克斯-2或考克斯-1的血管收缩性降低，导致考克斯-1介导的内皮依赖性收缩受到抑制，IC 50值远低于考克斯-1。此外，我们的数据表明，塞来昔布的这种作用可能是由其他一些考克斯-2抑制剂，如NS 398共享。(c)2012爱思唯尔有限公司版权所有。
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 IC50 of celecoxib obtained in COX-2 (-/-) abdominal aorta was only similar to 0.364 mu M. 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 (1 alpha) in COX-2 (-/-) aortas, but also caused a reduction in the contraction evoked by PGI(2), by the alpha(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 IC50 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. (c) 2012 Elsevier B.V. All rights reserved.