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 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.
Gorenflo
Matthias
M
Department of Pediatric Cardiology, Mannheim University of Heidelberg, Heidelberg, Germany. matthias.gorenflo@med.uni-heidelberg.de
Ullmann
Michael V
MV
Herpel
Esther
E
Neumayer
Stephan
S
Dieckmann
Ralf
R
Demirakca
Sueha
S
Klimpel
Homa
H
Hagl
Siegfried
S
Gebhard
Martha Maria
MM
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D006984:Hypertrophy / Q000188:drug therapy; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011652:Pulmonary Circulation; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D044023:Receptor, Endothelin B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D042461:Vascular Endothelial Growth Factor A; D000077868:Atrasentan