Atrasentan Treatment of Pulmonary Vascular Disease in Piglets With Increased Pulmonary Blood Flow

We studied the effect of chronic endothelin A receptor blockade by atrasentan on the pulmonary endothelin-1 system and vascular endothelial growth factor (VEGF) expression in piglets with high pulmonary blood flow. Twenty-five 4-week-old piglets with high pulmonary blood flow were randomized to three groups: sham operated (n = 8), placebo (water) (n = 7), or treatment with atrasentan (2 mg/kg per day) (n = 10). After 3 months, mean pulmonary arterial pressure (PAP) was higher in the placebo group than in the sham group [18 ± 2 mm Hg versus 14 ± 1 mm Hg; P< 0.05 (ANOVA)]. Atrasentan treatment was associated with lower cardiac output, PAP (14 ± 1 mm Hg), and medial wall thickness of pulmonary arteries (diameter: 50-150 μM) compared with placebo [13.6 ± 3.0% versus 18.1 ± 4.2%; P< 0.05 (ANOVA)]. Quantitative real-time polymerase chain reaction for endothelin-1, endothelin B receptor, and endothelin-converting enzyme-1 mRNA in lung tissue did not differ. However, immunostaining as well as mRNA for VEGF were lower in atrasentan-treated animals (relative gene expression: atrasentan versus placebo: 0.8 ± 0.3 versus 1.5 ± 0.3; P= 0.009). Atrasentan treatment effectively reduces medial hypertrophy in piglets with chronic pulmonary hyperperfusion. Chronic endothelin A receptor blockade by atrasentan may interfere with the expression of VEGF.