Sitaxsentan for the prevention of experimental shunt-induced pulmonary hypertension.

Abstract

We previously reported on the partial prevention of experimental shunt-induced pulmonary arterial hypertension (PAH) by the nonselective endothelin (ET) ET-A/ET-B receptor antagonist bosentan. As the respective roles of the ET-A and ET-B receptor signaling in the pathobiology of the disease remain undefined, we investigated the effects of selective ET-A receptor blockade by sitaxsentan in the same early stage PAH model. Twenty-one 3-wk-old piglets were randomized to placebo or sitaxsentan therapy (1.5 mg/kg/d), after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and real-time-quantitative-PCR for ET-1, angiopoietin-1, and bone morphogenetic 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 ET-1, ET-B receptor, and angiopoietin-1, and a decreased expression of BMPR-2 and BMPR-1A. Pretreatment with sitaxsentan prevented shunt-induced increase in PVR and decreased medial thickness by 64%. Sitaxsentan therapy completely prevented the decreased expression of BMPR-2 and limited the overexpression of ET-1, ET-B and angiopoietin-1, and the decreased expression of BMPR-1A. In conclusion, selective ET-A receptor blockade partially prevents shunt-induced PAH.

• Authors: Benoit Rondelet, François Kerbaul, Gabriela Flores Vivian, Ives Hubloue, Sandrine Huez, Pierre Fesler, Myriam Remmelink, Serge Brimiouille, Isabelle Salmon, Robert Naeije
• Journal: Pediatric research (Pediatr Res) Vol. 61 Issue 3 Pg. 284-8 (Mar 2007) ISSN: 0031-3998 [Print] United States
• PMID: 17314684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-1
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Isoxazoles
• RNA, Messenger
• Thiophenes
• Bone Morphogenetic Protein Receptors
• sitaxsentan

Topics

• Anastomosis, Surgical (adverse effects)
• Angiopoietin-1 (genetics)
• Animals
• Bone Morphogenetic Protein Receptors (genetics)
• Brachiocephalic Trunk (surgery)
• Disease Models, Animal
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (genetics)
• Hypertension, Pulmonary (etiology, genetics, prevention & control)
• Isoxazoles (pharmacology)
• Pulmonary Artery (surgery)
• RNA, Messenger (genetics, metabolism)
• Swine
• Thiophenes (pharmacology)