title: Relative role of heme nitrosylation and beta-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation.
abstract: To quantify the reactions of nitric oxide (NO) with hemoglobin under physiological conditions and to test models of NO transport on hemoglobin, we have developed an assay to measure NO-hemoglobin reaction products in normal volunteers, under basal conditions and during NO inhalation. NO inhalation markedly raised total nitrosylated hemoglobin levels, with a significant arterial-venous gradient, supporting a role for hemoglobin in the transport and delivery of NO. The predominant species accounting for this arterial-venous gradient is nitrosyl(heme)hemoglobin. NO breathing increases S-nitrosation of hemoglobin beta-chain cysteine 93, however only to a fraction of the level of nitrosyl(heme)hemoglobin and without a detectable arterial-venous gradient. A strong correlation between methemoglobin and plasma nitrate formation was observed, suggesting that NO metabolism is a primary physiological cause of hemoglobin oxidation. Our results demonstrate that NO-heme reaction pathways predominate in vivo, NO binding to heme groups is a rapidly reversible process, and S-nitrosohemoglobin formation is probably not a primary transport mechanism for NO but may facilitate NO release from heme.
authors.affiliation: Critical Care Medicine Department of the Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. mgladwin@nih.gov
authors.forename: M T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: F P
authors.initials: FP
authors.lastname: Ognibene
authors.forename: L K
authors.initials: LK
authors.lastname: Pannell
authors.forename: J S
authors.initials: JS
authors.lastname: Nichols
authors.forename: M E
authors.initials: ME
authors.lastname: Pease-Fye
authors.forename: J H
authors.initials: JH
authors.lastname: Shelhamer
authors.forename: A N
authors.initials: AN
authors.lastname: Schechter
mesh_terms: D000280:Administration, Inhalation; D003545:Cysteine; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008163:Luminescent Measurements; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D009573:Nitrites / Q000097:blood; D009603:Nitroso Compounds / Q000097:blood*; D010126:Ozone; D011190:Potassium Cyanide / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D006454:Hemoglobins; D009566:Nitrates; D009573:Nitrites; D009603:Nitroso Compounds; D009569:Nitric Oxide; D006418:Heme; D010126:Ozone; D003545:Cysteine; D011190:Potassium Cyanide