Peroxides (PX) are implicated in various retinopathies; some of their effects on retinal vasculature are partly mediated via prostanoids. Peroxidation can cause nonenzymatic oxidation of arachidonic acid to prostanoids termed isoprostanes. We postulated that the effects of PX on retinal vasomotor tone can be reproduced by the stable isoprostanes by acting via common mediators. During peroxidation the isoprostane 8-iso-PGF2α was abundantly produced in retina of NB more than of A pig 8-iso-PGF2α caused effective vasoconstriction (EC50: 2.1 nM) in NB more than A, as seen with PX (eg. H2O2) but contrary to constrictor prostaglandins, PGE2 and PGF2α. Because PX can activate synthesis of the constrictor endothelin (ET-1), we evaluated its role; ET-1 converting enzyme inhibitor, phosphoramidon, as well as ETA (BQ-485) but not ETB receptor (BQ-788) antagonists blocked 8-iso-PGF2α-induced vasoconstriction. The role of TXA2 which can mediate some effects of ET-1 and PX was also assessed; PX, ET-1 and 8-iso-PGF2α stimulated TXA2 formation, and TXA2 synthase and receptor blockers (CGS13,080 and L670,596) inhibited vasoconstriction elicited by all tested agents. In conclusion: 1) retinal vasoconstriction in response to oxidant stress is consistent with production of isoprostanes, the effects of which are greater in NB than A; and 2) this vasoconstriction to F2 isoprostanes is independent of PGE2 and PGF2α receptors, but is secondary to TXA2 formation via activation of ET-1 synthesis. Inhibition of effects of the stable isoprostanes may be beneficial in ischemic retinopathies (especially in preterm NB) once oxidation has been initiated.
