title: Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.
abstract: We previously showed that newborn piglets who develop pulmonary hypertension during exposure to chronic hypoxia have diminished pulmonary vascular nitric oxide (NO) production and evidence of endothelial NO synthase (eNOS) uncoupling (Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Am J Respir Cell Mol Biol 53: 255-264, 2015). Tetrahydrobiopterin (BH4) is a cofactor that promotes eNOS coupling. Current clinical strategies typically invoke initiating treatment after the diagnosis of pulmonary hypertension, rather than prophylactically. The major purpose of this study was to determine whether starting treatment with an oral BH4compound, sapropterin dihydrochloride (sapropterin), after the onset of pulmonary hypertension would recouple eNOS in the pulmonary vasculature and ameliorate disease progression in chronically hypoxic piglets. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received oral sapropterin starting on day 3 of hypoxia and continued throughout an additional 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios (a measure of eNOS coupling), NO production, and superoxide (O2·-) generation. Although higher than in normoxic controls, pulmonary vascular resistance was lower in sapropterin-treated hypoxic piglets than in untreated hypoxic piglets. Consistent with eNOS recoupling, eNOS dimer-to-monomer ratios and NO production were greater and O2·-generation was less in pulmonary arteries from sapropterin-treated than untreated hypoxic animals. When started after disease onset, oral sapropterin treatment inhibits chronic hypoxia-induced pulmonary hypertension at least in part by recoupling eNOS in the pulmonary vasculature of newborn piglets. Rescue treatment with sapropterin may be an effective strategy to inhibit further development of pulmonary hypertension in newborn infants suffering from chronic cardiopulmonary conditions associated with episodes of prolonged hypoxia.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Anna
authors.initials: A
authors.lastname: Dikalova
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, New York, New York.
authors.forename: Judy L
authors.initials: JL
authors.lastname: Aschner
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pediatrics, the University of Utah School of Medicine, Salt Lake City, Utah; and.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kaplowitz
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Marshall
authors.initials: M
authors.lastname: Summar
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pediatrics, the University of Utah School of Medicine, Salt Lake City, Utah; and candice.fike@hsc.utah.edu.
authors.forename: Candice D
authors.initials: CD
authors.lastname: Fike
mesh_terms: D000284:Administration, Oral; D000818:Animals; D062186:Arterial Pressure; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015687:Cell Hypoxia; D004353:Drug Evaluation, Preclinical; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology; D034421:Sus scrofa
chemical_list: D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin
keywords: nitric oxide signaling; pulmonary resistance arteries; sapropterin dihydrochloride; superoxide