Augmented Vasoconstriction and Thromboxane Formation by 15-F2t-Isoprostane (8-Iso-Prostaglandin F2α) in Immature Pig Periventricular Brain Microvessels
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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-F2t-isoprostane (15-F2t-IsoP) (8-iso-prostaglandin F2α) on periventricular region during development.
Methods—Effects of 15-F2t-IsoP on periventricular microvessels of fetal, newborn, and juvenile pigs were studied by video imaging and digital analysis techniques. Thromboxane formation and intracellular Ca2+ were measured by radioimmunoassay and by using the fluorescent indicator fura 2-AM.
Results—15-F2t-IsoP–mediated constriction of periventricular microvessels decreased as a function of age such that in the fetus it was ≈2.5-fold greater than in juvenile pigs. 15-F2t-IsoP evoked more thromboxane formation in the fetus than in the newborn, which was greater than that in the juvenile periventricular region; this was associated with immunoreactive thromboxane A2 (TXA2) synthase expression in the fetus that was greater than that in newborn pigs, which was greater than that in juvenile pigs. 15-F2t-IsoP–induced vasoconstriction was markedly inhibited by TXA2 synthase and receptor blockers (CGS12970 and L670596). Vasoconstrictor effects of the TXA2 mimetic U46619 on fetal, neonatal, and juvenile periventricular microvessels did not differ. 15-F2t-IsoP increased TXA2 synthesis by activating Ca2+ influx through non–voltage-gated channels in endothelial cells (SK&F96365 sensitive) and N-type voltage-gated channels (ω-conotoxin sensitive) in astrocytes; smooth muscle cells were not responsive to 15-F2t-IsoP but generated Ca2+ transients to U46619 via L-type voltage-sensitive channels.
Conclusions—15-F2t-IsoP causes periventricular brain region vasoconstriction in the fetus that is greater than that in the newborn, which in turn is greater than that in the juvenile due to greater TXA2 formation generated through distinct stimulatory pathways, including from endothelial and astroglial cells. The resulting hemodynamic compromise may contribute to the increased vulnerability of the periventricular brain areas to oxidant stress–induced injury in immature subjects.
- Received August 27, 1999.
- Revision received October 28, 1999.
- Accepted November 1, 1999.
- Copyright © 2000 by American Heart Association