Abstract 2964: Association Of Sitaxsentan And Sildenafil For The Prevention Of Overcirculation-induced Experimental Pulmonary Arterial Hypertension.
Introduction: Endothelin-1 (ET-1) and phosphodiesterase-5 play indivividually a major role in the pathogenesis of pulmonary arterial hypertension (PAH). The selective endothelin receptor-A blocker sitaxsentan1 or the phosphodiesterase-5 inhibitor sildenafil2, as a mono-therapy, have been shown to, partially, prevent overcirculation-induced experimental PAH and the associated arteriolar remodelling. We expected that a combined therapy with an association of sitaxsentan and sildenafil may be more effective in prevention of hemodynamic changes and remodelling associated with PAH.
Methods and results: Twenty-four 3-week-old piglets were randomized to placebo, to sitaxsentan therapy (1.5 mg/kg/day), to sitaxsentan (1.5 mg/kg/day) and sildenafil (0.75 mg/kg, 3 times/day) as combined therapy 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 endothelin-1, angiopoietin-1 and bone morphogenic protein receptor-2 pathways.
Conclusions: Combined therapy by sitaxsentan and sildenafil limited the increase in PVR and in medial thickness. This effects are associated with a reduction of the over-expression of endothelin-1 and the down-expression of BMPR-2.