title: Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury.
abstract: Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg(-1)·day(-1)) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with N(ω)-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg(-1)·day(-1)) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands. g.t.m.wagenaar@lumc.nl
authors.forename: Gerry T M
authors.initials: GT
authors.lastname: Wagenaar
authors.forename: El Houari
authors.initials: el H
authors.lastname: Laghmani
authors.forename: Yvonne P
authors.initials: YP
authors.lastname: de Visser
authors.forename: Rozemarijn M A
authors.initials: RM
authors.lastname: Sengers
authors.forename: Paul
authors.initials: P
authors.lastname: Steendijk
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Walther
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D065627:Familial Primary Pulmonary Hypertension; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D018496:Hyperoxia / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000254:growth & development; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010666:Phenylpropionates / Q000008:administration & dosage / Q000627:therapeutic use*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000254:growth & development; D011724:Pyridazines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D013997:Time Factors
chemical_list: D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan; D019331:NG-Nitroarginine Methyl Ester