title: Nitric oxide transport on sickle cell hemoglobin: where does it bind?
abstract: We have recently reported that nitric oxide inhalation in individuals with sickle cell anemia increases the level of NO bound to hemoglobin, with the development of an arterial-venous gradient, suggesting delivery to the tissues. A recent model suggests that nitric oxide, in addition to its well-known reaction with heme groups, reacts with the beta-globin chain cysteine 93 to form S-nitrosohemoglobin (SNO-Hb) and that SNO-Hb would preferentially release nitric oxide in the tissues and thus modulate blood flow. However, we have also recently determined that the primary NO hemoglobin adduct formed during NO breathing in normal (hemoglobin A) individuals is nitrosyl (heme)hemoglobin (HbFeIINO), with only a small amount of SNO-Hb formation. To determine whether the NO is transported as HbFeIINO or SNO-Hb in sickle cell individuals, which would have very different effects on sickle hemoglobin polymerization, we measured these two hemoglobin species in three sickle cell volunteers before and during a dose escalation of inhaled NO (40, 60, and 80 ppm). Similar to our previous observations in normal individuals, the predominant species formed was HbFeIINO, with a significant arterial-venous gradient. Minimal SNO-Hb was formed during NO breathing, a finding inconsistent with significant transport of NO using this pathway, but suggesting that this pathway exists. These results suggest that NO binding to heme groups is physiologically a rapidly reversible process, supporting a revised model of hemoglobin delivery of NO in the peripheral circulation and consistent with the possibility that NO delivery by hemoglobin may be therapeutically useful in sickle cell disease.
authors.affiliation: Critical Care Medicine Department, 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: J H
authors.initials: JH
authors.lastname: Shelhamer
authors.forename: M E
authors.initials: ME
authors.lastname: Pease-Fye
authors.forename: C T
authors.initials: CT
authors.lastname: Noguchi
authors.forename: G P
authors.initials: GP
authors.lastname: Rodgers
authors.forename: A N
authors.initials: AN
authors.lastname: Schechter
mesh_terms: D000755:Anemia, Sickle Cell / Q000378:metabolism* / Q000473:pathology*; D001665:Binding Sites; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008163:Luminescent Measurements; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D006451:Hemoglobin, Sickle; D006454:Hemoglobins; C103574:S-nitrosohemoglobin; C008657:nitrosyl hemoglobin; D009569:Nitric Oxide