Bosentan and Sildenafil reduce pulmonary arterial hypertension in rats induced by semaxanib and a low oxygen environment

Abstract

Previous work has demonstrated the development of increased pulmonary artery pressures, hypertrophy of the pulmonary arterial vascular smooth muscle, and proliferation of the endothelial vascular lumen in rats following extended exposure to hypoxia and VEGF‐receptor antagonists. We validated this model of pulmonary arterial hypertension (PAH) by evaluating its utility as a clinically relevant paradigm to determine the efficacy of test articles against PAH. Male SD rats (240–370 g) were kept inside a hypoxic tent. Atmospheric oxygen was reduced to 13.5% using an oxygen scrubber. Rats received a single dose of semaxanib (200 mg/kg, s.c.) and were maintained inside the tent for 3 weeks. Rats received oral doses of vehicle (20% cyclodextrin, 10mL/kg once daily), bosentan (BS‐ 300mg/kg once daily) or sildenafil (SL‐ 30mg/kg twice daily). At day 21, pulmonary and systemic arterial pressures and thoracic organ weights were measured. BS and SL‐treated rats exhibited systolic, diastolic and mean pulmonary arterial pressures (21 and 19; 16 and 15; 18 and 17 mmHg, respectively) that were significantly lower compared to the vehicle (30, 22 and 26 mmHg, respectively). There was a trend toward decreased right ventricle to left ventricle weight ratio when comparing BS and SL with the vehicle. There were no significant differences in mean arterial pressure among rats treated with BS and SL as compared to vehicle. In summary, oral administration of BS and SL reduces PAH induced semaxanib and a low oxygen environment in a clinically relevant model.