title: The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension.
abstract: OBJECTIVE
  Oxidative stress is implicated in the pathology of pulmonary arterial hypertension (PAH). Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for PAH, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in PAH and investigate whether vardenafil affects oxidative stress levels while improving PAH.
  
  
  RESULTS
  Sprague-Dawley rats with monocrotaline-induced PAH were administered oral vardenafil 1 mg kg⁻¹ day⁻¹ for 21 days (n = 12). Treatment-naive patients (n = 15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry, and assessments of oxidative/anti-oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats), vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output (CO). In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling, and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2α and 3-nitrotyrosine, and significantly increased nitric oxide (NO) levels in rats and patients. Furthermore, vardenafil significantly increased endothelial NO synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue.
  
  
  CONCLUSIONS
  Vardenafil reduces oxidative stress in rats and humans while improving PAH, warranting investigation of oxidative stress pathways as targets for PAH therapy.
authors: Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors: You-Fei
authors: YF
authors: Fan
authors: Rui
authors: R
authors: Zhang
authors: Xin
authors: X
authors: Jiang
authors: Li
authors: L
authors: Wen
authors: Dan-Chen
authors: DC
authors: Wu
authors: Dong
authors: D
authors: Liu
authors: Ping
authors: P
authors: Yuan
authors: Yu-Lin
authors: YL
authors: Wang
authors: Zhi-Cheng
authors: ZC
authors: Jing
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000627:therapeutic use; D014227:Triazines / Q000627:therapeutic use; D000069058:Vardenafil Dihydrochloride; D055815:Young Adult
chemical_list: D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D013450:Sulfones; D014227:Triazines; D009569:Nitric Oxide; D000069058:Vardenafil Dihydrochloride; D016686:Monocrotaline
keywords: Oxidative stress; Phosphodiesterase-5 inhibitor; Pulmonary arterial hypertension; Vardenafil; Vascular remodelling