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: Gerry T M Wagenaar, Rozemarijn M A Sengers, El Houari Laghmani, Xueyu Chen, Melissa P H A Lindeboom, Anton J M Roks, Gert Folkerts, Frans J Walther
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 307 Issue 3 Pg. L261-72 (Aug 01 2014) ISSN: 1522-1504 [Electronic] United States
• PMID: 24951776 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Angiotensin II Type 2 Receptor Blockers
• Imidazoles
• Ligands
• Pyridines
• Receptor, Angiotensin, Type 2
• PD 123319
• Fibrin

Topics

• Angiotensin II Type 2 Receptor Blockers (pharmacology)
• Animals
• Animals, Newborn
• Bronchopulmonary Dysplasia (drug therapy, metabolism, pathology)
• Fibrin (metabolism)
• Heart Injuries (drug therapy, metabolism, pathology)
• Hyperoxia (metabolism, pathology)
• Hypertrophy, Right Ventricular (drug therapy, metabolism, pathology)
• Imidazoles (pharmacology)
• Ligands
• Lung Injury (drug therapy, metabolism, pathology)
• Pneumonia (drug therapy, metabolism, pathology)
• Pulmonary Alveoli (drug effects, metabolism, pathology)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Angiotensin, Type 2 (metabolism)