Document Detail

Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension.
MedLine Citation:
PMID:  20693396     Owner:  NLM     Status:  MEDLINE    
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.
Benoit Rondelet; Laurence Dewachter; François Kerbaul; Céline Dewachter; Ives Hubloue; Pierre Fesler; Stephane Franck; Myriam Remmelink; Serge Brimioulle; Robert Naeije
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-06
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-04     Completed Date:  2010-11-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1118-23     Citation Subset:  IM    
Laboratory of Physiology, Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium.
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MeSH Terms
Angiopoietin-1 / metabolism
Bone Morphogenetic Protein Receptors, Type II / metabolism
Disease Models, Animal
Drug Therapy, Combination
Endothelin-1 / metabolism
Hypertension, Pulmonary / physiopathology,  prevention & control*
Isoxazoles / pharmacology,  therapeutic use*
Phosphodiesterase 5 Inhibitors / pharmacology,  therapeutic use*
Piperazines / pharmacology,  therapeutic use*
Pulmonary Artery / surgery
Pulmonary Circulation / drug effects*
Purines / pharmacology,  therapeutic use
Receptors, Endothelin / antagonists & inhibitors
Subclavian Artery / surgery
Sulfones / pharmacology,  therapeutic use*
Thiophenes / pharmacology,  therapeutic use*
Treatment Outcome
Reg. No./Substance:
0/Angiopoietin-1; 0/Endothelin-1; 0/Isoxazoles; 0/Phosphodiesterase 5 Inhibitors; 0/Piperazines; 0/Purines; 0/Receptors, Endothelin; 0/Sulfones; 0/Thiophenes; 0/sitaxsentan; 139755-83-2/sildenafil; EC Morphogenetic Protein Receptors, Type II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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