Effects of NCX 226, a compound targeting endothelin receptors and NO pathway, on monocrotaline-induced pulmonary hypertension and bleomycin-induced lung fibrosis models

Background: NCX 226 is a novel nitric oxide (NO)-donating bosen- tan. NO is known to exert anti-inflammatory and anti-fibrotic actions and improve microcirculation. We tested the effects of NCX 226 in monocrotaline-induced pulmonary hypertension (PAH) in the rat and bleomycin-induced lung fibrosis in the mouse, in comparison with bosentan. Methods: PAH: monocrotaline s.c. was administered to Sprague– Dawley rats then treated orally with test compounds (NCX 226 and bosentan in equimolar doses to 100 and 300 mg/kg) for 21 days. Endpoints: right ventricular pressure (RVP) and cardiac mass ratio. Lung fibrosis: Bleomycin was instilled intra-tracheally in C57BL/6 mice then treated orally for 14 days with NCX 226 or bosentan (equimolar at 10 and 30 mg/kg). Endpoints: airways resistance, histo- logical (collagen, microvascular density, arterial dilation) and biochemical analyses. Results: PAH: NCX 226 and bosentan reduced RVP but only NCX 226 had significant reductions in weight ratio of right ventricle/left ventri- cle + sectum. Both compounds did not affect systolic blood pressure. Lung fibrosis: Both test drugs prevented bleomycin-induced airway stiffness, being NCX 226 better. High dose NCX 226 was significantly more effective than equimolar bosentan in reducing lung tissue levels of myeloperoxidase (10.9, 4.8*# and 6.9* mU/mg prot), TGF-b (357.5, 134*# and 200.6* pg/mg prot) and thiobarbituric-acid reactive sub- stances (10, 4.4*# and 6.6* nmol/mg prot); values for vehicle, 37 mg/ kg NCX 226 and 30 mg/kg bosentan, respectively (p \ 0.01 vs. vehi- cle*or equimolar bosentan#). Both compounds decreased lung sclerosis and inflammation-induced vasculogenesis. Conclusion: NCX 226 and bosentan were active in the two models. NCX 226 showed improved efficacy over bosentan on RVP and cardiac mass ratio in PAH and in reducing key inflammatory parameters (e.g., leukocyte infiltration, TGF-b and oxidative stress) in lung fibrosis, confirming a potential beneficial role for NO in these pathologies.