Hou Xin, Roberts L Jackson, Gobeil Fernand, Taber DouglasF, Kanai Kazuo, Abran Daniel, Brault Sonia, Checchin Daniella, Sennlaub Florian, Lachapelle Pierre, Varma DayaR, Chemtob Sylvain
Centre de Recherche de l'Hôpital Sainte-Justine, Department of Pediatrics and Department of Pharmacology, Université de Montréal, 3175 Côte Sainte-Catherine, PQ, H3T 1C5, Montréal, Canada.
Free Radic Biol Med. 2004 Jan 15;36(2):163-72. doi: 10.1016/j.freeradbiomed.2003.10.024.
F2-isoprostanes (F2-IsoP's) are biologically active prostanoids formed by free radical-mediated peroxidation of arachidonic acid. Four different F2-IsoP regioisomers (5-, 8-, 12-, and 15-series), each comprising eight racemic diastereomers, total 64 compounds. Information regarding the biological activity of IsoP's is largely limited to 15-F2t-IsoP (8-iso-PGF2alpha). We recently demonstrated that 15-F2t-IsoP and its metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP, evoked vasoconstriction and TXA2 generation in retina and brain microvasculature. We have now examined and compared the biological activities of a series of recently synthesized new 5-, 12-, and 15-series F2-IsoP isomers in pig retinal and brain microvasculature. We hereby show that other 15-series F2-IsoP isomers, 15-epi-15-F2t-IsoP, ent-15-F2t-IsoP, and ent-15-epi-15-F2t-IsoP, are also potent vasoconstrictors. The 12-series isomers tested, 12-F2t-IsoP and 12-epi-12-F2t-IsoP, also caused marked vasoconstriction. Of the 5-series isomers tested, 5-F2t-IsoP and 5-epi-5-F2t-IsoP possessed no vasomotor properties, whereas ent-5-F2t-IsoP caused modest vasoconstriction. The vasoconstriction of ent-5-F2t-IsoP, 12-F2t-IsoP, and 12-epi-12-F2t-IsoP was abolished by removal of the endothelium, by TXA2 synthase and receptor inhibitor (CGS12970, L670,596), and by receptor-mediated Ca2+ channel blockade (SK & F96365); correspondingly, these isomers increased TXB2 formation by activating Ca2+ influx (detected with fura 2-AM) through non-voltage-dependent receptor-mediated Ca2+ entry (SK & F96365 sensitive) in endothelial cells. In conclusion, as seen with 15-F2t-IsoP, ent-5-F2t-IsoP, 12-F2t-IsoP, and 12-epi-12-F2t-IsoP constricted both retinal and brain microvessels by inducing endothelium-dependent TXA2 synthesis. These new findings broaden the scope of our understanding regarding the potential involvement of F2-IsoP's as mediators of oxidant injury.
F2-异前列腺素（F2-IsoP）是由自由基介导的花生四烯酸过氧化反应生成的具有生物活性的前列腺素类物质。有四种不同的F2-IsoP区域异构体（5-、8-、12-和15-系列），每种异构体包含八个外消旋非对映异构体，共计64种化合物。关于异前列腺素生物活性的信息在很大程度上仅限于15-F2t-IsoP（8-异前列腺素F2α）。我们最近证明，15-F2t-IsoP及其代谢产物2,3-二降-5,6-二氢-15-F2t-IsoP可引起视网膜和脑微血管的血管收缩及血栓素A2生成。我们现在研究并比较了一系列最近合成的新型5-、12-和15-系列F2-IsoP异构体在猪视网膜和脑微血管中的生物活性。我们在此表明，其他15-系列F2-IsoP异构体，15-表-15-F2t-IsoP、对映体-15-F2t-IsoP和对映体-15-表-15-F2t-IsoP，也是有效的血管收缩剂。所测试的12-系列异构体，12-F2t-IsoP和12-表-12-F2t-IsoP，也引起了明显的血管收缩。在所测试的5-系列异构体中，5-F2t-IsoP和5-表-5-F2t-IsoP不具有血管舒缩特性，而对映体-5-F2t-IsoP引起适度的血管收缩。对映体-5-F2t-IsoP、12-F2t-IsoP和12-表-12-F2t-IsoP的血管收缩作用可通过去除内皮、使用血栓素A2合酶和受体抑制剂（CGS12970、L670596）以及受体介导的钙通道阻滞（SK&F96365）来消除；相应地，这些异构体通过激活内皮细胞中依赖于非电压依赖性受体介导的钙内流（对SK&F96365敏感）引起的钙内流（用fura 2-AM检测）来增加血栓素B2的形成。总之，正如15-F2t-IsoP所见，对映体-5-F2t-IsoP、12-F2t-IsoP和12-表-12-F2t-IsoP通过诱导内皮依赖性血栓素A2合成而使视网膜和脑微血管收缩。这些新发现拓宽了我们对F2-异前列腺素作为氧化损伤介质潜在作用的理解范围。
