Sitaxsentan for the prevention of experimental shunt-induced pulmonary hypertension.
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.
Rondelet
Benoit
B
Laboratory of Physiology, Department of Cardiac Surgery, Hôpital Erasme, Université Libre de B-1070 Bruxelles, Belgium. benoit.rondelet@ulb.ac.be
Kerbaul
François
F
Vivian
Gabriela Flores
GF
Hubloue
Ives
I
Huez
Sandrine
S
Fesler
Pierre
P
Remmelink
Myriam
M
Brimiouille
Serge
S
Salmon
Isabelle
I
Naeije
Robert
R
D000714:Anastomosis, Surgical / Q000009:adverse effects; D042683:Angiopoietin-1 / Q000235:genetics; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics; D016122:Brachiocephalic Trunk / Q000601:surgery; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D007555:Isoxazoles / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000601:surgery; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology*
D042683:Angiopoietin-1; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D012333:RNA, Messenger; D013876:Thiophenes; D052004:Bone Morphogenetic Protein Receptors; C106276:sitaxsentan