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Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

¹Clinical Integrative Biology, Sunnybrook Research Institute, ²Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, and Departments of ³Pediatrics and ⁴Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 26 April 2007 ; accepted in final form 10 December 2007

Xanthine oxidase (XO)-derived reactive oxygen species (ROS) formation contributes to experimental chronic hypoxic pulmonary hypertension in adults, but its role in neonatal pulmonary hypertension has received little attention. In rats chronically exposed to hypoxia (13% O₂) for 14 days from birth, we examined the effects of ROS scavengers (U74389G 10 mg·kg^–1·day^–1 or Tempol 100 mg·kg^–1·day^–1 ip) or a XO inhibitor, Allopurinol (50 mg·kg^–1·day^–1 ip). Both ROS scavengers limited oxidative stress in the lung and attenuated hypoxia-induced vascular remodeling, confirming a critical role for ROS in this model. However, both interventions also significantly inhibited somatic growth and normal cellular proliferation in distal air spaces. Hypoxia-exposed pups had evidence of increased serum and lung XO activity, increased vascular XO-derived superoxide production, and vascular nitrotyrosine formation. These changes were all prevented by treatment with Allopurinol, which also attenuated hypoxia-induced vascular remodeling and partially reversed inhibited endothelium-dependent arterial relaxation, without affecting normal growth and proliferation. Collectively, our findings suggest that XO-derived superoxide induces endothelial dysfunction, thus impairing pulmonary arterial relaxation, and contributes to vascular remodeling in hypoxia-exposed neonatal rats. Due to the potential for adverse effects on normal growth, targeting XO may represent a superior "antioxidant" strategy to ROS scavengers for neonates with pulmonary hypertension.

antioxidants; allopurinol; U74389G; Tempol; 8-isoprostane

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