The Role Of Endothelial Nitric Oxide Synthase Expression In The Development Of Pulmonary Hypertension In Chronically Hypoxic Infant Swine

Abstract

Objective: Our goal was to determine the role of pulmonary endothelial nitric oxide synthase expression in the development of pulmonary hypertension in infants with congenital cyanotic heart disease. Methods: Two groups of 4-week-old piglets were studied. In one group, the piglets were raised in an environment of 10% oxygen from 2 days of age (cyanotic, n = 6), and in the other group the piglets were raised at room air (control, n = 5). Pulmonary hemodynamics were measured in vivo for each animal, and peripheral lung biopsy specimens were obtained for Western blot analysis with the use of antiendothelial nitric oxide synthase antibody and for activity analysis with the use of the tritiated l-arginine assay. Results: The piglets in the chronically hypoxic group had significant increases in mean pulmonary arterial pressure (44.0 ± 3.8 mm Hg vs 14.8 ± 1.2 mm Hg in controls, p = 0.0007) and pulmonary vascular resistance (7272.0 ± 871.1 dyne · cm · sec -5 vs 1844.5 ± 271.2 dyne · cm · sec -5in controls, p = 0.002). These changes in the pulmonary hemodynamics of the hypoxic piglets were accompanied by a twofold increase in the expression of pulmonary endothelial nitric oxide synthase ( p = 0.0043) but no corresponding increase in nitric oxide synthase activity. Conclusions: Raising infant piglets in an environment of 10% oxygen for 4 weeks results in significant pulmonary arterial hypertension accompanied by increased expression of nitric oxide synthase within the lung endothelium. Furthermore, the increased levels of nitric oxide synthase within the lungs of the hypoxic swine were not accompanied by a proportional increase in enzyme activity. These findings suggest that the development of pulmonary hypertension in infants with congenital cyanotic disease is not due to decreased expression of endothelial nitric oxide synthase, but instead may be related to a decreased ability of the enzyme to produce sufficient nitric oxide. (J Thorac Cardiovasc Surg 1998;115:343-50)