title: Pulmonary haemodynamics are correlated with intimal lesions in a rat model of severe PAH: attenuation of pulmonary vascular remodelling with ambrisentan.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is characterized by obstructive lesions and vasoconstriction of the pulmonary arteries. Early therapeutic interventions with vasodilator drugs are thought to be beneficial in PAH. However, it remains unknown whether the severity of intimal obstruction is associated with increased pulmonary arterial pressure and whether reduction of vasoconstriction in the earlier stage by these drugs has a beneficial effect. Therefore, the aims of this study were to investigate these issues in a rat model of severe PAH. Methods A rat model of severe PAH was created by injection of a vascular endothelial growth factor receptor blocker in combination with hypoxia for the first 3 weeks followed by normoxia for the next 9 weeks. To assess intimal obstruction, "the pulmonary artery occlusion index (PAOI)" was developed to digitize all lesions. The small pulmonary arteries were assessed by this index, and the association between right ventricular systolic pressure (RVSP) and PAOI was investigated. An endothelin receptor antagonist, ambrisentan, was administered by gavage to rats during either hypoxia (Prevention study group, n=25) or normoxia (Early treatment group, n=15).
  
  
  RESULTS
  PAOI showed a positive correlation with RVSP, and both RVSP and PAOI increased gradually over time. There were no severe occlusive lesions in either group, but the density of partially occlusive lesions was significantly decreased in the Prevention study group.
  
  
  CONCLUSIONS
  A novel PAOI index was developed, and this index was strongly correlated with RVSP. Furthermore, ambrisentan reduced luminal occlusive lesions more effectively when treatment was given during the first 2 weeks of hypoxia.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan. sakaos@faculty.chiba-u.jp.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sakao
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kato
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Naito
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Jujo
authors.affiliation: Department of Respirology, National Hospital Organization Chiba Medical Center, Chiba, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan