Peroxynitrite mediates right-ventricular dysfunction in nitric oxide-exposed juvenile rats.
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.
Jankov
Robert P
RP
Clinical Integrative Biology, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. robert.jankov@sunnybrook.ca
Lewis
Patricia
P
Kantores
Crystal
C
Ivanovska
Julijana
J
Xu
Emily Z
EZ
Van Vliet
Todd
T
Lee
Alvin H
AH
Tanswell
A Keith
AK
McNamara
Patrick J
PJ
D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary; D017380:Hypertrophy, Right Ventricular; D008665:Metalloporphyrins / Q000494:pharmacology; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000627:therapeutic use; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014655:Vascular Resistance; D018497:Ventricular Dysfunction, Right / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II