title: Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy.
abstract: Hypoxia is a common challenge to the fetus, promoting a physiological defence to redistribute blood flow towards the brain and away from peripheral circulations. During acute hypoxia, reactive oxygen species (ROS) interact with nitric oxide (NO) to provide an oxidant tone. This contributes to the mechanisms redistributing the fetal cardiac output, although the source of ROS is unknown. Here, we investigated whether ROS derived from xanthine oxidase (XO) contribute to the fetal peripheral vasoconstrictor response to hypoxia via interaction with NO-dependent mechanisms. Pregnant ewes and their fetuses were surgically prepared for long-term recording at 118 days of gestation (term approximately 145 days). After 5 days of recovery, mothers were infused i.v. for 30 min with either vehicle (n = 11), low dose (30 mg kg(-1), n = 5) or high dose (150 mg kg(-1), n = 9) allopurinol, or high dose allopurinol with fetal NO blockade (n = 6). Following allopurinol treatment, fetal hypoxia was induced by reducing maternal inspired O2 such that fetal basal P aO 2 decreased approximately by 50% for 30 min. Allopurinol inhibited the increase in fetal plasma uric acid and suppressed the fetal femoral vasoconstrictor, glycaemic and lactate acidaemic responses during hypoxia (all P < 0.05), effects that were restored to control levels with fetal NO blockade. The data provide evidence for the activation of fetal XO in vivo during hypoxia and for XO-derived ROS in contributing to the fetal peripheral vasoconstriction, part of the fetal defence to hypoxia. The data are of significance to the understanding of the physiological control of the fetal cardiovascular system during hypoxic stress. The findings are also of clinical relevance in the context of obstetric trials in which allopurinol is being administered to pregnant women when the fetus shows signs of hypoxic distress.
authors.affiliation: Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK. dag26@cam.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Kane
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Hansell
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Herrera
authors.forename: Beth J
authors.initials: BJ
authors.lastname: Allison
authors.forename: Youguo
authors.initials: Y
authors.lastname: Niu
authors.forename: Kirsty L
authors.initials: KL
authors.lastname: Brain
authors.forename: Joepe J
authors.initials: JJ
authors.lastname: Kaandorp
authors.forename: Jan B
authors.initials: JB
authors.lastname: Derks
authors.forename: Dino A
authors.initials: DA
authors.lastname: Giussani
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005318:Fetal Heart / Q000503:physiopathology*; D005311:Fetal Hypoxia / Q000097:blood / Q000503:physiopathology*; D005865:Gestational Age; D006339:Heart Rate; D019344:Lactic Acid / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000097:blood; D012039:Regional Blood Flow; D012756:Sheep; D014527:Uric Acid / Q000097:blood; D014661:Vasoconstriction; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014527:Uric Acid; D009569:Nitric Oxide; D019344:Lactic Acid; D000493:Allopurinol; D014969:Xanthine Oxidase; D010100:Oxygen