title: Red blood cell membrane-facilitated release of nitrite-derived nitric oxide bioactivity.
abstract: The reduction of nitrite by deoxyhemoglobin to nitric oxide (NO) has been proposed as a mechanism for the transfer of NO bioactivity from the red blood cell (RBC) to the vasculature. This transfer can increase vascular dilatation. The major challenge to this hypothesis is the very efficient scavenging of NO by hemoglobin, which prevents the release of NO from RBCs. Previous studies indicate that the reaction of nitrite with deoxyhemoglobin produces two metastable intermediates involving nitrite bound to deoxyhemoglobin and a hybrid intermediate [Hb(II)NO(+) ↔ Hb(III)NO] where the nitrite is reduced, but unavailable to react with hemoglobin. We have now shown how unique properties of these intermediates provide a pathway for the release of NO bioactivity from RBCs. The high membrane affinity of these intermediates (>100-fold greater than that of deoxyhemoglobin) places these intermediates on the membrane. Furthermore, membrane-induced conformational changes of the nitrite-reacted intermediates facilitate the release of NO from the hybrid intermediate and nitrite from the nitrite-bound intermediate. Increased membrane affinity, coupled with facilitated dissociation of NO and nitrite from the membrane-bound intermediates, provides the first realistic mechanism for the potential release of NO and nitrite from the RBC and their potential transfer to the vasculature.
authors.affiliation: Molecular Dynamics Section, National Institute on Aging, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Salgado
authors.affiliation: Molecular Dynamics Section, National Institute on Aging, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.
authors.forename: Zeling
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Molecular Dynamics Section, National Institute on Aging, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.
authors.forename: Enika
authors.initials: E
authors.lastname: Nagababu
authors.affiliation: Molecular Dynamics Section, National Institute on Aging, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.
authors.forename: Joy G
authors.initials: JG
authors.lastname: Mohanty
authors.affiliation: Molecular Dynamics Section, National Institute on Aging, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rifkind
mesh_terms: D004910:Erythrocyte Membrane / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D006454:Hemoglobins; D009573:Nitrites; D009569:Nitric Oxide; C100003:deoxyhemoglobin