title: Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PH) is a fatal disease marked by excessive pulmonary vascular cell proliferation. Patients with idiopathic PH express endothelin-1 (ET-1) at high levels in their lungs. As the activation of both types of ET-1 receptor (ETA and ETB) leads to increased generation of superoxide and hydrogen peroxide, this may contribute to the severe oxidative stress found in PH patients. As a number of pathways may induce oxidative stress, the particular role of ET-1 remains unclear. The aim of this study was to determine whether inhibition of ET-1 signaling could reduce pulmonary oxidative stress and attenuate the progression of disease in rats with occlusive-angioproliferative PH induced by a single dose of SU5416 (200 mg/kg) and subsequent exposure to hypoxia for 21 days. Using this regimen, animals developed severe PH as evidenced by a progressive increase in right-ventricle (RV) peak systolic pressure (RVPSP), severe RV hypertrophy, and pulmonary endothelial and smooth muscle cell proliferation, resulting in plexiform vasculopathy. PH rats also had increased oxidative stress, correlating with endothelial nitric oxide synthase uncoupling and NADPH oxidase activation, leading to enhanced protein nitration and increases in markers of vascular remodeling. Treatment with the combined ET receptor antagonist bosentan (250 mg/kg/day; day 10 to 21) prevented further increase in RVPSP and RV hypertrophy, decreased ETA/ETB protein levels, reduced oxidative stress and protein nitration, and resulted in marked attenuation of pulmonary vascular cell proliferation. We conclude that inhibition of ET-1 signaling significantly attenuates the oxidative and nitrosative stress associated with PH and prevents its progression.
authors.affiliation: Center for Clinical Pharmacology and Vascular Medicine Institute, Department of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Rafikova
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Frank
authors.initials: F
authors.lastname: Schneider
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
mesh_terms: D000818:Animals; D000077300:Bosentan; D004195:Disease Models, Animal; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism*; D015538:Nitrosation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D009566:Nitrates; D013449:Sulfonamides; D000077300:Bosentan