title: Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension.
abstract: Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. 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.
authors.affiliation: Laboratory of Physiology, Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Rondelet
authors.forename: Laurence
authors.initials: L
authors.lastname: Dewachter
authors.forename: François
authors.initials: F
authors.lastname: Kerbaul
authors.forename: Céline
authors.initials: C
authors.lastname: Dewachter
authors.forename: Ives
authors.initials: I
authors.lastname: Hubloue
authors.forename: Pierre
authors.initials: P
authors.lastname: Fesler
authors.forename: Stephane
authors.initials: S
authors.lastname: Franck
authors.forename: Myriam
authors.initials: M
authors.lastname: Remmelink
authors.forename: Serge
authors.initials: S
authors.lastname: Brimioulle
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000517:prevention & control*; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000601:surgery; D011652:Pulmonary Circulation / Q000187:drug effects*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013348:Subclavian Artery / Q000601:surgery; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D042683:Angiopoietin-1; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013876:Thiophenes; D000068677:Sildenafil Citrate; D052006:Bone Morphogenetic Protein Receptors, Type II; C106276:sitaxsentan