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Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of right ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect right ventricular function.<\/jats:p>","DOI":"10.1152\/ajpheart.00418.2010","type":"journal-article","created":{"date-parts":[[2010,8,7]],"date-time":"2010-08-07T02:49:56Z","timestamp":1281149396000},"page":"H1118-H1123","source":"Crossref","is-referenced-by-count":15,"title":["Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension"],"prefix":"10.1152","volume":"299","author":[{"given":"Benoit","family":"Rondelet","sequence":"first","affiliation":[{"name":"Laboratory of Physiology, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Libre de Bruxelles, Brussels, Belgium;"},{"name":"Heart and Lung Transplantation Unit, Departments of Cardiac and Thoracic Surgery, H\u00f4pital Erasme, Universit\u00e9 Libre de Bruxelles, Brussels, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Dewachter","sequence":"additional","affiliation":[{"name":"Laboratory of 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