Concomitant activation of functionally opposing prostacyclin and thromboxane prostanoid receptors by cyclo-oxygenase-1-mediated prostacyclin synthesis in mouse arteries
Concomitant activation of functionally opposing prostacyclin and thromboxane prostanoid receptors by cyclo-oxygenase-1-mediated prostacyclin synthesis in mouse arteries
复制标题
环加氧酶 1 介导的小鼠动脉中前列环素合成同时激活功能相反的前列环素和血栓素前列腺素受体
DOI：
10.1113/expphysiol.2011.063784
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发表时间：
2012-07-01
影响因子：
2.7
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合酶-1(COX-1)是否通过合成前列环素(PGI2)来介导小鼠动脉的扩张，如果是，PGI2(IP)受体是如何发挥作用的，以及血栓素前列腺素(TP)受体是否参与了这一过程。从野生型小鼠或COX-1缺陷(COX-1-/-)小鼠分离肠系膜动脉。用等长力测定法测定对COX底物花生四烯酸(AA)的血管舒缩反应，用高效液相色谱仪和酶免疫法分别测定PGI2代谢物6-keto-PGF1a的体外产生和血浆水平。结果表明，AA可引起内皮依赖性6-keto-PGF1a的产生，其松弛作用可被IP或TP受体拮抗或增强。此外，IP受体阻断导致对AA的反应收缩(在没有合酶抑制之后)，这被伴随的TP受体拮抗剂所阻止。同时，COX-1-/-或COX-1抑制可抑制6-keto-PGF1a的体外产生，并减少AA引起的松弛或收缩。实时定量聚合酶链式反应显示，TP受体mRNAs的表达水平与肠系膜动脉相似，而IP受体mRNAs在肠系膜动脉的分支中的表达水平高于主干。此外，拮抗IP受体可增强PGI2引起的颈动脉收缩。此外，我们注意到COX-1-/-小鼠的基础血浆6-keto-PGF1a水平降低。这些结果表明COX-1介导的内皮PGI2合成具有明显的血管扩张作用，提示IP和TP受体的功能相反同时介导了对PGI2的血管舒缩反应，IP受体的扩张活性被TP受体的血管收缩作用所削弱，反之亦然。
This study aimed to determine whether cyclo-oxygenase-1 (COX-1) mediates dilatation of mouse arteries via synthesis of prostacyclin (PGI2) and, if so, how PGI2 (IP) receptors contribute and whether thromboxane prostanoid (TP) receptors are implicated in the process. Mesenteric arteries were isolated from wild-type mice or mice with COX-1 deficiency (COX-1-/-). The vasomotor reaction to the COX substrate arachidonic acid (AA) was determined with isometric force measurement, while the in vitro production or the plasma level of the PGI2 metabolite 6-keto-PGF1a was analysed with high-performance liquid chromatographymass spectroscopy or enzyme immunoassay, respectively. Results showed that AA, which evoked endothelium-dependent 6-keto-PGF1a production, elicited relaxation that was inhibited or enhanced by antagonizing IP or TP receptors, respectively. Also, IP receptor blockade resulted in contraction in response to AA (following NO synthase inhibition), which was prevented by a concomitant TP receptor antagonism. Meanwhile, COX-1-/- or COX-1 inhibition abolished the in vitro 6-keto-PGF1a production and reduced the relaxation or contraction observed with AA. Real-time PCR showed that whereas TP receptor mRNAs were detected at similar levels, IP receptor mRNAs were present at higher levels in the branches than in the main stem of the mesenteric artery. In addition, antagonizing the IP receptors enhanced the contraction evoked by PGI2 in the carotid artery. Also, we noted that COX-1-/- mice had a reduced basal plasma 6-keto-PGF1a level. These results demonstrate an explicit vasodilator role for COX-1-mediated endothelial PGI2 synthesis and suggest that the functionally opposing IP and TP receptors concomitantly mediate the vasomotor reaction to PGI2, with the dilator activity of IP receptors being compromised by the vasoconstrictor effect of TP receptors and vice versa.