Abstract / Summary
The effects of ONO-6950, a novel dual antagonist of cysteinyl leukotriene 1 (CysLT1) and 2 (CysLT2) receptors, were examined in a monocrotaline-induced rat model of pulmonary arterial hypertension (PAH). The effects were compared with those of montelukast (selective CysLT1 receptor antagonist), bosentan (endothelin receptor antagonist), and imatinib (tyrosine kinase inhibitor). In the rat PAH model, ONO-6950 (10, 30, or 100 mg/kg, p.o.) and bosentan (50 mg/kg, p.o.) significantly ameliorated right ventricular hypertrophy and elevation of right ventricular pressure, both indices of PAH, whereas montelukast showed only limited efficacy. Histopathological evaluation revealed that ONO-6950 showed a weak trend toward improvement in pulmonary vascular remodeling and inflammatory cell infiltration in lung tissue. Furthermore, ONO-6950 and imatinib similarly prolonged survival in the rat PAH model. These results demonstrate that ONO-6950 is an orally active dual CysLT1/CysLT2 receptor antagonist that may provide a novel therapeutic option for PAH.