Isomer-specific contractile effects of a series of synthetic F2-isoprostanes on retinal and cerebral microvasculature

F-2-isoprostanes (F-2-IsoP's) are biologically active prostanoids formed by free radical-mediated peroxidation of arachidonic acid. Four different F-2-lsoP 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-F-2t- IsoP (8-iso-PGF(2alpha)). We recently demonstrated that 15-F-2t-IsoP and its metabolite, 2,3-dinor-5,6-dihydro-15-F(2)t-IsoP, evoked vasoconstriction and TXA(2) 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 F-2-IsoP isomers in pig retinal and brain microvasculature. We hereby show that other 15-series F-2-IsoP isomers, 15-epi-15-F(2)t-IsoP, ent-15-F(2)t-IsoP, and ent-15-epi-15-F(2)t-IsoP, are also potent vasoconstrictors. The 12-series isomers tested, 12-F-2t-IsoP and 12-epi-12-F-2t-IsoP, also caused marked vasoconstriction. Of the 5-series isomers tested, 5-F-2t-IsoP and 5-epi-5-F(2-)IsoP possessed no vasomotor properties, whereas ent-5-F-2t-IsoP caused modest vasoconstriction. The vasoconstriction of ent-5-F-2t-IsoP, 12-F-2t-IsoP, and 12-epi-12-F-2t-IsoP was abolished by removal of the endothelium, by TXA(2) synthase and receptor inhibitor (CGS12970, L670,596), and by receptor-mediated Ca2+ channel blockade (SKF96365); 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-F-2t-IsoP, ent-5-F-2t-IsoP, 12-F-2t-IsoP, and 12-epi-12-F-2t-IsoP constricted both retinal and brain microvessels by inducing endothelium-dependent TXA(2) synthesis. These new findings broaden the scope of our understanding regarding the potential involvement of F-2-IsoP's as mediators of oxidant injury. (C) 2003 Elsevier Inc. All rights reserved.