A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension.
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.
McMahon
Timothy J
TJ
Department of Medicine and Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Ahearn
Gregory S
GS
Moya
Martin P
MP
Gow
Andrew J
AJ
Huang
Yuh-Chin T
YC
Luchsinger
Benjamin P
BP
Nudelman
Raphael
R
Yan
Yun
Y
Krichman
Abigail D
AD
Bashore
Thomas M
TM
Califf
Robert M
RM
Singel
David J
DJ
Piantadosi
Claude A
CA
Tapson
Victor F
VF
Stamler
Jonathan S
JS
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
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