title: A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension.
abstract: The mechanism by which hypoxia [low partial pressure of O(2) (pO(2))] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO(2-)governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). S-nitrosothiol (SNO)-deficient RBCs produce impaired vasodilator responses in vitro and exaggerated pulmonary vasoconstrictor responses in vivo and are defective in oxygenating the blood. RBCs from hypoxemic patients with elevated pulmonary arterial pressure (PAP) exhibit a similar FeNO/SNO imbalance and are thus deficient in pO(2)-coupled vasoregulation. Chemical restoration of SNO-Hb levels in both animals and patients restores the vasodilator activity of RBCs, and this activity is associated with improved oxygenation and lower PAPs.
authors.affiliation: Department of Medicine and Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McMahon
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Ahearn
authors.forename: Martin P
authors.initials: MP
authors.lastname: Moya
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Yuh-Chin T
authors.initials: YC
authors.lastname: Huang
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Luchsinger
authors.forename: Raphael
authors.initials: R
authors.lastname: Nudelman
authors.forename: Yun
authors.initials: Y
authors.lastname: Yan
authors.forename: Abigail D
authors.initials: AD
authors.lastname: Krichman
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bashore
authors.forename: Robert M
authors.initials: RM
authors.lastname: Califf
authors.forename: David J
authors.initials: DJ
authors.lastname: Singel
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.forename: Victor F
authors.initials: VF
authors.lastname: Tapson
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006454:Hemoglobins / Q000172:deficiency*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D011817:Rabbits; D026403:S-Nitrosothiols / Q000494:pharmacology*; D034421:Sus scrofa
chemical_list: D006454:Hemoglobins; D009573:Nitrites; D009589:Nitrogen Oxides; D026403:S-Nitrosothiols; C103574:S-nitrosohemoglobin; D009569:Nitric Oxide; C073661:dinitrosyl iron complex; C032712:ethyl nitrite; D007501:Iron; D010100:Oxygen