Transforming growth factor-β (TGF-β) inhibition is an
investigational therapy for
pulmonary arterial hypertension with promising results in experimental studies. The present work compared this approach with
endothelin-receptor blockade and evaluated the effects of combined administration.
Pulmonary arterial hypertension was induced by single
monocrotaline injection (60 mg/kg) in 75 Wistar rats and 15 rats served as controls. Intervention groups consisted of treatment with an antibody against TGF-β-
ligand,
bosentan, both or none, initiated four weeks after
monocrotaline injection. Right ventricular systolic pressure, pulmonary
vascular remodeling, and exercise tolerance were evaluated eight weeks after
monocrotaline injection. Either treatment, alone or in combination, lowered mortality. Comparable efficacy was found in the three treatment groups in terms of right ventricular systolic pressure (~45% decrease) and
hypertrophy (~30% decrease), as well as exercise capacity. The three treatment groups equally ameliorated pulmonary
vascular remodeling, evidenced by decreased vessel-wall thickness (in vessels 50-200 μm) and a smaller number of pre-capillary arterioles (< 50 μm) with a muscularized media. Treatment either with an antibody against TGF-β or with
endothelin receptor blockade are equally effective in experimental
pulmonary hypertension. Their combination provides no added benefit, indicating common mechanisms of action.