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Updated: Jun 10, 2026
Induction of Right Ventricular Failure by Pulmonary Artery Constriction and Evaluation of Right Ventricular Function in Mice
Published on: May 13, 2019
Peroxynitrite mediates right-ventricular dysfunction in nitric oxide-exposed juvenile rats
Robert P Jankov1, Patricia Lewis, Crystal Kantores
1Clinical Integrative Biology, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. robert.jankov@sunnybrook.ca
Insights
Inhaled nitric oxide (iNO) for infant pulmonary hypertension may harm the right ventricle by increasing peroxynitrite. A peroxynitrite scavenger normalized heart function in a rat model.
Area of Science:
- Cardiovascular Research
- Pediatric Pulmonology
- Neonatal Physiology
Background:
- Chronic pulmonary hypertension in children leads to right-ventricular (RV) failure and mortality.
- Inhaled nitric oxide (iNO) is a current treatment for neonatal pulmonary hypertension.
- Established models of chronic neonatal pulmonary hypertension are crucial for studying therapeutic effects.
Purpose of the Study:
- To investigate the effects of iNO on established chronic hypoxic pulmonary hypertension in juvenile rats.
- To assess iNO's impact on RV function, vascular remodeling, and molecular markers in a neonatal pulmonary hypertension model.
Main Methods:
- Juvenile rats were exposed to hypoxia (13% O(2)) or air from day 1 to 21.
- Inhaled nitric oxide (20 ppm) was administered from day 14 to 21.
- Right ventricular output, vascular remodeling, nitrotyrosine, apoptosis, and nitric oxide synthase expression were measured. A peroxynitrite decomposition catalyst (FeTPPS) was used concurrently in some groups.
Main Results:
- iNO reduced pulmonary vascular resistance in hypoxic rats but did not improve RV output or reverse vascular remodeling.
- RV output significantly decreased in air-exposed pups treated with iNO.
- Increased nitrotyrosine, apoptosis, and nitric oxide synthase expression were observed in RV tissue of iNO-treated pups (both air and hypoxia).
- FeTPPS treatment prevented apoptosis and normalized RV output in iNO-exposed animals.
Conclusions:
- Inhaled nitric oxide may adversely affect the right ventricle in neonatal pulmonary hypertension models.
- Increased local peroxynitrite generation appears to mediate iNO's detrimental effects on the RV.
- Targeting peroxynitrite may mitigate iNO-induced RV dysfunction.
Abstract:
Chronic pulmonary hypertension in infancy and childhood frequently culminates in right-ventricular (RV) failure and early death. Current management may include prolonged treatment with inhaled nitric oxide (iNO). Our objective was to examine the effects of iNO on established chronic hypoxic pulmonary hypertension in juvenile rats, a model of chronic neonatal pulmonary hypertension characterized by increased pulmonary vascular resistance, vascular remodeling (RV hypertrophy and arterial medial wall thickening), and significant RV dysfunction. Pups were exposed to air or hypoxia (13% O(2)) from postnatal day 1 to 21 while receiving iNO (20 ppm) from day 14 to 21. In hypoxia-exposed animals, treatment with iNO decreased pulmonary vascular resistance, but did not augment RV output or reverse vascular remodeling. In addition, RV output was significantly reduced in air-exposed iNO-treated pups. Nitrotyrosine (a marker of peroxynitrite-mediated reactions), apoptosis, and expression of nitric oxide synthases 1 and 2 were increased in RV (but not left-ventricular) tissue from both air- and hypoxia-exposed pups treated with iNO. Concurrent treatment with a peroxynitrite decomposition catalyst (FeTPPS, 30 mg/kg/day, ip) prevented apoptosis and completely normalized RV output in iNO-exposed animals. Our results provide the first evidence that iNO may adversely impact the right ventricle through increased local generation of peroxynitrite.
