15-F_2t-isoprostane (15-F_2t-IsoP), also termed 8-isoprostaglandin F_2α, is one of a series of prostanoids formed by free radical-mediated peroxidation of arachidonic acid and exerts potent biological actions such as vasoconstriction. We recently demonstrated that 15-F_2t-IsoP is metabolized in humans to a major metabolite, 2,3-dinor-5,6-dihydro-15-F_2t-IsoP (15-F_2t-IsoP-M). 15-F_2t-IsoP-M can also potentially be formed as a product of free radical-induced oxidation of the low abundance fatty acid γ-linolenic acid. We confirmed that 15-F_2t-IsoP-M is generated during oxidation of γ-linolenic acid and explored whether it may exhibit biological activity. 15-F_2t-IsoP-M caused marked constriction of porcine surface retinal and intraparenchymal brain microvessels, comparable to that observed with 15-F_2t-IsoP. These effects were associated with increased thromboxane A₂(TXA₂) formation and were virtually abolished by TXA₂-synthase and -receptor inhibitors (CGS-12970 and L-670596). Vasoconstriction induced by either 15-F_2t-IsoP or 15-F_2t-IsoP-M on perfused ocular choroid was also abrogated by TXA₂-synthase inhibition as well as by removal of endothelium. Similar to 15-F_2t-IsoP, 15-F_2t-IsoP-M evoked vasoconstriction and TXA₂generation by activating Ca²⁺influx from nonvoltage-gated channels (SK&F96365 sensitive) in the retina and from both nonvoltage- and N-type voltage-gated Ca²⁺channels (ω-conotoxin MVIIA sensitive), respectively, in brain endothelial and astroglial cells; smooth muscle cells were unresponsive to both agents. Cross-desensitization experiments further suggest that 15-F_2t-IsoP and 15-F_2t-IsoP-M act on the same receptor mechanism. Findings reveal a novel concept by which a β-oxidation metabolite of 15-F_2t-IsoP that can also be formed by nonenzymatic oxidation of γ-linolenic acid is equivalently bioactive to 15-F_2t-IsoP and may prolong the vascular actions of F₂-IsoPs.

Publications with shared reference:

0 publications found