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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/L777    most recent 00047.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Belik, J. Articles by Jankov, R. P. PubMed PubMed Citation Articles by Belik, J. Articles by Jankov, R. P.

Chronic hypercapnia downregulates arginase expression and activity and increases pulmonary arterial smooth muscle relaxation in the newborn rat

¹Physiology and Experimental Medicine Program, The Hospital for Sick Children Research Institute, ; ²Clinical Integrative Biology, Sunnybrook Research Institute, ; Divisions of ³Neonatology and ; ⁴Respiratory Medicine, Department of Pediatrics, and ; ⁵Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and ; ⁶Maastricht University, Maastricht, Holland

Submitted 12 February 2009 ; accepted in final form 4 August 2009

In rats, chronic hypercapnia has been reported to ameliorate hypoxia-induced pulmonary hypertension in newborn and adult and to enhance endothelium-dependent vasorelaxation in adult pulmonary arteries. The underlying mechanisms accounting for chronic hypercapnia-induced improvements in pulmonary vascular function are not understood. Hypothesizing that downregulation of arginase activity may be contributory, we examined relaxation responses and arginase activity and expression in pulmonary arteries from newborn rats that were exposed (from birth to 14 days) to either mild-to-moderate (5.5% inhaled CO₂) or severe (10% CO₂) hypercapnia with either normoxia or hypoxia (13% O₂). Pulmonary arteries from pups exposed to normoxia and chronic hypercapnia (5.5 or 10% CO₂) contracted less in response to a thromboxane A₂ analog, U-46619, and showed enhanced endothelium-dependent (but not independent) relaxation compared with arteries from normocapnic pups (P < 0.01). Parallel with these changes, arginase activity and arginase I (but not II) expression in lung and pulmonary arterial tissue were significantly decreased (P < 0.05). Exposure to 10% CO₂ significantly increased (P < 0.01) pulmonary arterial tissue nitric oxide (nitrite) generation. In pups chronically exposed to hypoxia (13% O₂), severe hypercapnia (10% CO₂) significantly (P < 0.05) enhanced endothelium-dependent relaxation, increased nitric oxide generation, and decreased arginase activity but not expression. We conclude that chronic hypercapnia-induced downregulation of lung arginase expression and/or activity may reduce pulmonary vascular resistance by enhancing nitric oxide generation and thus endothelium-dependent relaxation. This mechanism may explain some of the beneficial effects of chronic hypercapnia on experimental pulmonary hypertension.

pulmonary vascular resistance; nitric oxide; hypoxia