title: L-Citrulline ameliorates chronic hypoxia-induced pulmonary hypertension in newborn piglets.
abstract: Newborn piglets develop pulmonary hypertension and have diminished pulmonary vascular nitric oxide (NO) production when exposed to chronic hypoxia. NO is produced by endothelial NO synthase (eNOS) in the pulmonary vascular endothelium using l-arginine as a substrate and producing l-citrulline as a byproduct. l-Citrulline is metabolized to l-arginine by two enzymes that are colocated with eNOS in pulmonary vascular endothelial cells. The purpose of this study was to determine whether oral supplementation with l-citrulline during exposure of newborn piglets to 10 days of chronic hypoxia would prevent the development of pulmonary hypertension and increase pulmonary NO production. A total of 17 hypoxic and 17 normoxic control piglets were studied. Six of the 17 hypoxic piglets were supplemented with oral l-citrulline starting on the first day of hypoxia. l-Citrulline supplementation was provided orally twice a day. After 10 days of hypoxia or normoxia, the animals were anesthetized, hemodynamic measurements were performed, and the lungs were perfused in situ. Pulmonary arterial pressure and pulmonary vascular resistance were significantly lower in hypoxic animals treated with l-citrulline compared with untreated hypoxic animals (P < 0.001). In vivo exhaled NO production (P = 0.03) and nitrite/nitrate accumulation in the perfusate of isolated lungs (P = 0.04) were significantly higher in l-citrulline-treated hypoxic animals compared with untreated hypoxic animals. l-Citrulline supplementation ameliorated the development of pulmonary hypertension and increased NO production in piglets exposed to chronic hypoxia. We speculate that l-citrulline may benefit neonates exposed to prolonged periods of hypoxia from cardiac or pulmonary causes.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, Nashville, TN, USA.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Ananthakrishnan
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Barr
authors.forename: Marshall L
authors.initials: ML
authors.lastname: Summar
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Smith
authors.forename: Mark
authors.initials: M
authors.lastname: Kaplowitz
authors.forename: Gary
authors.initials: G
authors.lastname: Cunningham
authors.forename: Jordan
authors.initials: J
authors.lastname: Magarik
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Candice D
authors.initials: CD
authors.lastname: Fike
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002908:Chronic Disease; D002956:Citrulline / Q000494:pharmacology*; D045853:Exhalation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010477:Perfusion; D011312:Pressure; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D034421:Sus scrofa
chemical_list: D000596:Amino Acids; D009566:Nitrates; D002956:Citrulline; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III