Effects of ONO-6950, a Novel Dual Cysteinyl Leukotriene 1 and 2 Receptor Antagonist, in a Rat Model of Pulmonary Arterial Hypertension

Abstract

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.