Isomer-specific contractile effects of a series of synthetic f2-isoprostanes on retinal and cerebral microvasculature.
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.
Hou
Xin
X
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.
Roberts
L Jackson
LJ
Gobeil
Fernand
F
Taber
DouglasF
D
Kanai
Kazuo
K
Abran
Daniel
D
Brault
Sonia
S
Checchin
Daniella
D
Sennlaub
Florian
F
Lachapelle
Pierre
P
Varma
DayaR
D
Chemtob
Sylvain
S
D000818:Animals; D001921:Brain / Q000098:blood supply*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D028441:F2-Isoprostanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007536:Isomerism; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D012160:Retina / Q000502:physiology*; D013552:Swine; D013928:Thromboxane A2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D028441:F2-Isoprostanes; D013928:Thromboxane A2; D002118:Calcium