title: A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep.
abstract: Virtually nothing is known about the effects on fetal physiology of xanthine oxidase inhibition. This is despite maternal treatment with the xanthine oxidase inhibitor allopurinol being considered in human complicated pregnancy to protect the infant’s brain from excessive generation of ROS.We investigated the in vivo effects of maternal treatment with allopurinol on fetal cardiovascular function in ovine pregnancy in late gestation. Under anaesthesia, pregnant ewes and their singleton fetus were instrumented with vascular catheters and flow probes around an umbilical and a fetal femoral artery at 118±1 dGA (days of gestational age; termca. 145 days). Five days later, mothers were infused I.V. with either vehicle (n =11) or allopurinol (n =10). Fetal cardiovascular function was stimulated with increasing bolus doses of phenylephrine (PE) following maternal vehicle or allopurinol. The effects of maternal allopurinol on maternal and fetal cardiovascular function were also investigated following fetal NO blockade (n =6) or fetal β1-adrenergic antagonism (n =7). Maternal allopurinol led to significant increases in fetal heart rate, umbilical blood flow and umbilical vascular conductance, effects abolished by fetal β1-adrenergic antagonism but not by fetal NO blockade. Maternal allopurinol impaired fetal α1-adrenergic pressor and femoral vasopressor responses and enhanced the gain of the fetal cardiac baroreflex. These effects of maternal allopurinol were restored to control levels during fetal NO blockade. Maternal treatment with allopurinol induced maternal hypotension, tachycardia and acid–base disturbance. We conclude that maternal treatment with allopurinol alters in vivo maternal, umbilical and fetal vascular function via mechanisms involving NO and β1-adrenergic stimulation. The evidence suggests that the use of allopurinol in clinical practice should be approached with caution.
authors.affiliation: Department of Physiology Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Herrera
authors.forename: A D
authors.initials: AD
authors.lastname: Kane
authors.forename: J A
authors.initials: JA
authors.lastname: Hansell
authors.forename: A S
authors.initials: AS
authors.lastname: Thakor
authors.forename: B J
authors.initials: BJ
authors.lastname: Allison
authors.forename: Y
authors.initials: Y
authors.lastname: Niu
authors.forename: D A
authors.initials: DA
authors.lastname: Giussani
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000201:enzymology; D005865:Gestational Age; D006340:Heart Rate, Fetal / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012756:Sheep; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D014527:Uric Acid; D009569:Nitric Oxide; D000493:Allopurinol; D014969:Xanthine Oxidase