Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Pharmacology & Pharmacy, Cardiovascular System & Cardiology, lung, pulmonary hypertension, endothelin-1, VEGF, CONGENITAL HEART-DISEASE, ENDOTHELIAL GROWTH-FACTOR, A-RECEPTOR, DIAPHRAGMATIC-HERNIA, ENHANCED EXPRESSION, NEWBORN PIGLETS, HYPERTENSION, PRESSURE, LUNGS, OVERCIRCULATION, Animals, Atrasentan, Blood Pressure, Cardiac Output, Chronic Disease, Disease Models, Animal, Endothelin A Receptor Antagonists, Endothelin-1, Gene Expression Regulation, Hypertension, Pulmonary, Hypertrophy, Immunohistochemistry, Lung, Pulmonary Artery, Pulmonary Circulation, Pyrrolidines, RNA, Messenger, Random Allocation, Receptor, Endothelin B, Reverse Transcriptase Polymerase Chain Reaction, Swine, Vascular Endothelial Growth Factor A, Receptor, Endothelin A, 1102 Cardiorespiratory Medicine and Haematology, 1115 Pharmacology and Pharmaceutical Sciences, Cardiovascular System & Hematology
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 microM) 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.