Abstract
BACKGROUND: Newborns who live at high altitudes are chronically exposed to low oxygen levels, which may impair lung development and induce vascular remodeling, often resulting in pulmonary hypertension, right ventricular hypertrophy, and right heart failure. Nitric oxide has a critical role in mediating pulmonary vasodilation and supporting healthy lung development. The potential therapeutic role of long-term inhaled NO in hypoxia-induced pulmonary hypertension and right ventricular disease has not been determined. The objective of this study was to investigate the therapeutic effects of long-term inhaled NO in a mouse model of pulmonary hypertension in the context of impaired lung development. METHODS: Beginning on postnatal day 3 or 4, mice were exposed to either 21% or 11% inspired fraction of oxygen, with or without continuous inhaled NO at 10 ppm. This study assessed exhaled NO levels and plasma nitrite and nitrate concentrations on mice at the age of 2 to 3 months. Pulmonary hypertension, right ventricular hypertrophy, and cardiac function were evaluated using echocardiography and invasive hemodynamic measurements. Vascular and alveolar structure was analyzed by histology. RESULTS: Chronic hypoxia impaired lung development and caused pulmonary hypertension. Levels of exhaled NO and plasma nitrite and nitrate concentrations were reduced by chronic hypoxia. Long-term inhaled NO therapy restored NO biomarkers and improved pulmonary hypertension, right ventricular hypertrophy, and right ventricular function. However, hypoxia-induced alveolar and vascular rarefaction were unaffected by inhaled NO. CONCLUSIONS: These findings support further investigation of prolonged inhaled NO as a potential therapeutic strategy for conditions associated with chronic hypoxia, such as those experienced at high altitude.