title: Assessments of the chemistry and vasodilatory activity of nitrite with hemoglobin under physiologically relevant conditions.
abstract: Hypoxic vasodilation involves detection of the oxygen content of blood by a sensor, which rapidly transduces this signal into vasodilatory bioactivity. Current perspectives on the molecular mechanism of this function hold that hemoglobin (Hb) operates as both oxygen sensor and a condition-responsive NO reactor that regulates the dispensing of bioactivity through release of the NO group from the beta-cys93 S-nitroso derivative of Hb, SNO-Hb. A common path to the formation of SNO-Hb involves oxidative transfer of the NO-group from heme to thiol. We have previously reported that the reaction of nitrite with deoxy-Hb, which furnishes heme-Fe(II)NO, represents one attractive route for the formation of SNO-Hb. Recent literature, however, posits that the nitrite-reductase reaction of Hb might produce physiological vasodilatory effects through NO that evades trapping on heme-Fe(II) and may be stored before release as Fe(III)NO. In this article, we briefly review current perspectives in NO biology on the nitrite-reductase reaction of Hb. We report in vitro spectroscopic (UV/Vis, EPR) studies that are difficult to reconcile with suggestions that this reaction either generates a heme-Fe(III)NO reservoir or significantly liberates NO. We further show in bioassay experiments that combinations of nitrite and deoxy-Hb--under conditions that suppress SNO-Hb formation--exhibit no direct vasodilatory activity. These results help underscore the differences between physiological, RBC-regulated, hypoxic vasodilation versus pharmacological effects of exogenous nitrite.
authors.affiliation: Department of Chemistry, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Luchsinger
authors.forename: Eric N
authors.initials: EN
authors.lastname: Rich
authors.forename: Yun
authors.initials: Y
authors.lastname: Yan
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Williams
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.forename: David J
authors.initials: DJ
authors.lastname: Singel
mesh_terms: D015374:Biosensing Techniques; D004912:Erythrocytes / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D009572:Nitrite Reductases / Q000378:metabolism; D009573:Nitrites / Q000737:chemistry / Q000378:metabolism*; D015538:Nitrosation; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D013057:Spectrum Analysis; D013997:Time Factors; D014664:Vasodilation / Q000502:physiology*
chemical_list: D005290:Ferric Compounds; D005296:Ferrous Compounds; D006454:Hemoglobins; D009573:Nitrites; D006418:Heme; D009572:Nitrite Reductases; D010100:Oxygen