title: Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats.
abstract: Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg·kg(-1)·day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 μg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg·kg(-1)·day(-1)) in two 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 lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2-3 and PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.
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.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Rozemarijn M A
authors.initials: RM
authors.lastname: Sengers
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: El Houari
authors.initials: el H
authors.lastname: Laghmani
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Xueyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Melissa P H A
authors.initials: MP
authors.lastname: Lindeboom
authors.affiliation: Division of Vascular Disease and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Roks
authors.affiliation: Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; and.
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Walther
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005337:Fibrin / Q000378:metabolism; D006335:Heart Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D055370:Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C073402:PD 123319; D005337:Fibrin
keywords: angiotensin II type 2 receptor; bronchopulmonary dysplasia; lung inflammation; pulmonary hypertension; right ventricular hypertrophy