Peroxynitrite mediates right-ventricular dysfunction in nitric oxide-exposed juvenile rats

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.