title: Pulmonary arterial responses to reactive oxygen species are altered in newborn piglets with chronic hypoxia-induced pulmonary hypertension.
abstract: Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. ROS might mediate vascular responses, at least in part, by stimulating prostanoid production. Our goals were to determine whether the effect of ROS on vascular tone is altered in resistance pulmonary arteries (PRAs) of newborn piglets with chronic hypoxia-induced pulmonary hypertension and the role, if any, of prostanoids in ROS-mediated responses. In cannulated, pressurized PRA, ROS generated by xanthine (X) plus xanthine oxidase (XO) had minimal effect on vascular tone in control piglets but caused significant vasoconstriction in hypoxic piglets. Both cyclooxygenase inhibition with indomethacin and thromboxane synthase inhibition with dazoxiben significantly blunted constriction to X+XO in hypoxic PRA. X+XO increased prostacyclin production (70 ± 8%) by a greater degree than thromboxane production (50 ± 6%) in control PRA; this was not the case in hypoxic PRA where the increases in prostacyclin and thromboxane production were not statistically different (78 ± 13% versus 216 ± 93%, respectively). Thromboxane synthase expression was increased in PRA from hypoxic piglets, whereas prostacyclin synthase expression was similar in PRA from hypoxic and control piglets. Under conditions of chronic hypoxia, altered vascular responses to ROS may contribute to pulmonary hypertension by a mechanism that involves the prostanoid vasoconstrictor, thromboxane.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee 37232, USA. Candice.fike@vanderbilt.edu
authors.forename: Candice D
authors.initials: CD
authors.lastname: Fike
authors.forename: Judy L
authors.initials: JL
authors.lastname: Aschner
authors.forename: James C
authors.initials: JC
authors.lastname: Slaughter
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kaplowitz
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Pfister
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007213:Indomethacin / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018709:Statistics, Nonparametric; D034421:Sus scrofa; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D011453:Prostaglandins; D017382:Reactive Oxygen Species; C029166:dazoxiben; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; D007213:Indomethacin