Augmented vasoconstriction and thromboxane formation by 15-F-2t-isoprostane (8-iso-prostaglandin F-2 alpha) in immature pig periventricular brain microvessels

Background and Purpose-Oxidant stress, especially in the premature, plays a major role in the pathogenesis of hypoxic-ischemic encephalopathies mostly manifested in the periventricular region. We studied the vasomotor mode of actions of the peroxidation product 15-F-2t-isoprostane (15-F-2t-IsoP) (8- iso-prostaglandin F-2 alpha) On periventricular region during development. Methods-Effects of 15-F-2t-IsoP on periventricular microvessels of fetal, n ewborn, and juvenile pigs were studied by video imaging and digital analysi s techniques, Thromboxane formation and intracellular Ca2+ were measured by radioimmunoassay and by using the fluorescent indicator fura 2-AM. Results-15-F-2t-IsoP-mediated constriction of periventricular microvessels decreased as a function of age such that in the fetus it was approximate to 2.5-fold greater than in juvenile pigs, 15-F-2t-IsoP evoked more thromboxa ne formation in the fetus than in the newborn, which was greater than that in the juvenile periventricular region; this was associated with immunoreac tive thromboxane A(2) (TXA(2)) synthase expression in the fetus that was gr eater than that in newborn pigs, which was greater than that in juvenile pi gs. 15-F-2t-IsoP-induced vasoconstriction was markedly inhibited by TXA(2) synthase and receptor blockers (CGS12970 and L670596), Vasoconstrictor effe cts of the TXA(2) mimetic U46619 on fetal, neonatal, and juvenile periventr icular microvessels did not differ, 15-F-2t-IsoP increased TXA(2) synthesis by activating Ca2+ influx through non-voltage-gated channels in endothelia l cells (SK&F96365 sensitive) and N-type voltage-gated channels (omega-cono toxin sensitive) in astrocytes; smooth muscle cells were not responsive to 15-F-2t-IsoP but generated Ca-2t transients to U46619 via L-type voltage-se nsitive channels, Conclusions-15-F-2t-IsoP causes periventricular brain region vasoconstricti on in the fetus that is greater than that in the newborn, which in turn is greater than that in the juvenile due to greater TXA(2) formation generated through distinct stimulatory pathways, including from endothelial and astr oglial cells. The resulting hemodynamic compromise may contribute to the in creased vulnerability of the periventricular brain areas to oxidant stress- induced injury in immature subjects.