INCREASED PULMONARY BLOOD-FLOW PRODUCES ENDOTHELIAL-CELL DYSFUNCTION IN NEONATAL SWINE

Background. The mechanisms by which increased pulmonary blood now resu lts in pulmonary hypertension have not been determined. Methods. To de termine if increased pulmonary blood now produces endothelial dysfunct ion that precedes vascular remodeling and smooth muscle proliferation, neonatal swine (n = 12) (age, 6.1 +/- 0.5 days) underwent ligation of the left pulmonary artery (LPA) to increase blood now to the right lu ng. At 12 weeks of age, endothelium-dependent vasodilatation was asses sed by acetylcholine infusion and endothelium-independent vasodilatati on by inhaled nitric oxide (NO) in the LPA group and age-matched contr ols (CON) (n = 11). Results. Mean pulmonary artery pressure was 24.1 /- 3.0 mm Hg in the LPA group and 20.8 +/- 1.9 mm Hg in the CON group (p < 0.1). Pulmonary vascular resistance was 13.2 +/- 2.2 Wood units i n the LPA group and 5.8 +/- 0.8 Wood units in the CON group (p = 0.001 ). Acute occlusion of the left pulmonary artery in the CON group incre ased pulmonary vascular resistance to 6.9 +/- 3.9 Wood units (p = 0.04 ). Administration of acetylcholine in the CON group after preconstrict ion with the thromboxane A, analogue U46619 resulted in a 30.6% +/- 5. 4% decrease in pulmonary vascular resistance. In the LPA group, acetyl choline produced paradoxical vasoconstriction and a 15.4% +/- 4.1% inc rease in pulmonary vascular resistance (p < 0.001 versus CON) indicati ng loss of endothelium-dependent vasodilatation. Nitric oxide decrease d pulmonary vascular resistance by 41.9% +/- 3.3% in the CON group and 30.8% +/- 2.7% in the LPA group (p = 0.04 versus CON), indicating pre served endothelium-independent vasodilatation in both groups. Morphome tric analysis was performed in 4 animals from each group. Medial wall thickness as percent of external diameter of small arteries (<100 pm) was the same in both groups (6.4% +/- 0.4% in the LPA group versus 6.6 % +/- 0.4% in the CON animals; p > 0.1). Conclusions. Increased pulmon ary blood now in immature animals produces endothelial cell dysfunctio n with loss of endothelium-dependent vasodilatation before the onset o f pulmonary vascular remodeling. Subsequent smooth muscle proliferatio n may be mediated by endothelium-derived factors. (Ann Thorac Surg 199 8;66:1372-7) (C) 1998 by The Society of Thoracic Surgeons