Endothelin receptor (ETR) blockade combined with phosphodiesterase‐5 (PDE5) inhibition prevents right ventricular hypoxia in Pulmonary Hypertension

Abstract

BackgroundPulmonary hypertension (PH) may cause right ventricular (RV) hypoxia, which may contribute to RV failure.GoalTo study the effects of current PH therapies on the presence of hypoxia in the RV.MethodsPH was induced in Wistar rats by monocrotaline (MCT) (40 mg/kg). From day 14 to 28, rats were treated with Bosentan (ETR antagonist, 300 mg/kg/day), Sildenafil (PDE5 inhibitor, 10 mg/kg/day) or both (all n=3). Healthy rats served as controls (n=3). 1.5 hour prior to sacrifice hypoxyprobe (pimonidazole, 60 mg/kg) was administered i.v. Cryosections (5 μm) of the hearts were incubated with hypoxyprobe antibody and for succinate dehydrogenase (SDH) activity. RV capillary density and cardiomyocyte cross‐sectional area (CSA) were determined.ResultsPH significantly increased RV pimonidazole binding, and cardiomyocyte CSA, and decreased capillary density, and SDH activity (all p<0.05 vs control). Single treatment with Bosentan or Sildenafil had no effect, whereas combination treatment normalized all parameters (p<0.05 vs MCT rats). Pimonidazole binding related linearly to CSA (r=0.6), SDH activity (r=−0.7), and capillary density (r=−0.8) (all p<0.05).ConclusionHypoxia in the RV of PH rats is caused by cardiomyocyte hypertrophy, a lowering in mitochondrial activity and a diminished capillary density, and can be prevented by combining ETR blockade and PDE5 inhibition.