Abstract

Pulmonary arterial hypertension (PAH) is a life threatening disease that results in right ventricular failure. PRX-08066 is a selective 5-HT2B receptor antagonist that causes selective vasodilation of pulmonary arteries. In the current study, the effects of PRX-08066 were assessed using the monocrotaline (MCT) -induced PAH rat model. Male rats received 40 mg/kg of MCT or PBS and were treated orally twice a day with vehicle, 50 mg/kg or 100 mg/kg of PRX-08066 for 5 weeks. Pulmonary and cardiac functions were evaluated by hemodynamics, heart weight, MRI, pulmonary artery (PA) morphology and histology. Cardiac MRI demonstrated that PRX-08066 (100 mg/kg) significantly (P < 0.05) improved right ventricular ejection fraction. PRX-08066 significantly reduced peak PA pressure at 50 mg/kg and 100 mg/kg (P < 0.05, P < 0.01, respectively) compared to MCT control animals. PRX-08066 therapy also significantly reduced RV/body weight and RV/LV+Septum (P < 0.01, P < 0.001, respectively) compared to MCT treated animals. Morphometric assessment of pulmonary arterioles revealed a significant reduction in medial wall thickening and lumen occlusion associated with both doses of PRX-08066 (P < 0.01). The 5-HT2B receptor antagonist PRX-08066 significantly attenuated the elevation in PA pressure, RV hypertrophy, and maintained cardiac function. Pulmonary vascular remodeling was also diminished compared to MCT control rats. PRX-08066 prevents the severity of PAH in the MCT rat model.