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Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

¹Clinical Integrative Biology, Sunnybrook Research Institute; ²Lung Biology and ³Cardiovascular Programs, The Hospital for Sick Children Research Institute; and the Departments of ⁴Critical Care, ⁵Pediatrics, and ⁶Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 10 November 2005 ; accepted in final form 5 July 2006

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO₂) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO₂ would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO₂ was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O₂) or moderate hypoxia (13% O₂). 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% CO₂ (but not to 5.5% CO₂) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals (P < 0.05), whereas both concentrations of CO₂ normalized right ventricular performance. Exposure to 10% CO₂ 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 CO₂ on the lung and consequent modulating effects on the endothelin pathway.

carbon dioxide; endothelin; oxidant stress; 8-isoprostane; echocardiography

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