title: Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat.
abstract: Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO(2)) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO(2) would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO(2) was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O(2)) or moderate hypoxia (13% O(2)). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO(2) (but not to 5.5% CO(2)) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals (P < 0.05), whereas both concentrations of CO(2) normalized right ventricular performance. Exposure to 10% CO(2) attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO(2) on the lung and consequent modulating effects on the endothelin pathway.
authors.affiliation: Clinical Integrative Biology, Sunnybrook Research Institute, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.forename: Lilian
authors.initials: L
authors.lastname: Teixeira
authors.forename: Doreen
authors.initials: D
authors.lastname: Engelberts
authors.forename: Prashanth
authors.initials: P
authors.lastname: Murthy
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D002245:Carbon Dioxide / Q000097:blood / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006400:Hematocrit; D006935:Hypercapnia / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D007189:Indans / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D011247:Pregnancy; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007189:Indans; D002245:Carbon Dioxide; C098288:enrasentan; D010100:Oxygen