The efficacy of endothelin (ET) receptor antagonist bosentan in patients with 
severe pulmonary arterial hypertension (PAH) remains limited, partly because its 
higher doses for potential blockade of ET receptors have never been tested due 
to liver dysfunction. We hypothesized that rigorous blockade of ET receptors 
using the novel dual ET receptor antagonist macitentan would be effective in 
treating severe PAH without major side effects in a preclinical model 
appropriately representing the human disorder. In normal rats, 30 mg·kg·d of 
macitentan completely abolished big ET-1-induced increases in right ventricle 
(RV) systolic pressure. Adult male rats were injected with SU5416, a vascular 
endothelial growth factor blocker, and exposed to hypoxia for 3 weeks and then 
to normoxia for an additional 5 weeks (total 8 weeks). In intrapulmonary 
arterial rings isolated from rats with severe PAH, macitentan concentration 
dependently inhibited ET-1-induced contraction. Long-term treatment with 
macitentan (30 mg·kg·d, from week 3 to 8) reversed the high RV systolic pressure 
with preserved cardiac output. Development of RV hypertrophy, luminal occlusive 
lesions and medial wall thickening were also significantly improved without 
increasing serum levels of liver enzymes by macitentan. In conclusion, 
efficacious blockade of ET receptors with macitentan would reverse severe PAH 
without major adverse effects.