Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity

Gladwin, Mark T.; Schechter, Alan N.; Shelhamer, James H.; Pannell, Lewis K.; Conway, D.; Hrinczenko, Borys; Nichols, James S.; Pease-Fye, Margaret E.; Noguchi, Constance Tom; Rodgers, Griffin P.; Ognibene, Frederick P.

doi:10.1172/jci7637

Cited by 111 publications

(94 citation statements)

References 24 publications

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“…Recent studies demonstrating NO binding to haemoglobin (Gladwin et al, 1999) implicate another mechanism of action for NO in the regulation of vascular tone. Inhaled NO has been advocated as a possible therapy for ACS (Atz & Wessel, 1997), and clinical trials of inhaled NO in patients with acute respiratory distress syndrome are ongoing (Dellinger et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease

Morris¹,

Kuypers²,

Larkin³

et al. 2000

Br J Haematol

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To determine the effects of l‐arginine (l‐Arg) supplementation on nitric oxide metabolite (NOx) production, oral l‐Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso‐occlusive crisis (VOC). l‐Arg (0·1 g/kg) increased NOx formation by 18·8 ± 68% in normal controls, whereas steady‐state SCD patients demonstrated a paradoxical decrease in NOx of −16·7 ± 4% (P = 0·004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77·7 ± 103%, a response that was dose dependent. l‐Arg appears to be the rate‐limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.

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Section: Resultsmentioning

confidence: 99%

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease

Morris¹,

Kuypers²,

Larkin³

et al. 2000

Br J Haematol

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“…Bonaventura and co-workers have observed that S-nitrosylated Hb A and unpolymerized Hb S exhibit an increase in oxygen affinity, and that the presence of 30% SNO-Hb S decreases Hb S polymerization, even at high Hb S concentrations [15]. Formation of SNO-Hb has been linked to vasodilation [5], as well as increased oxygen affinity [16] both of which would indicate S-nitrosylated Hb S has potential to be an effective treatment for sickle cell disease. The current results suggest that a complex interplay of competing effects is potentially associated with thiol modification in Hb, in which the level and location of Cys modification need to be explicitly considered.…”

Section: Implications For No Binding and Reactivitymentioning

confidence: 99%

“…Nitric oxide has been implicated as a potential treatment for sickle cell disease (SCD), either by increasing the oxygen affinity of sickle cell erythrocytes or by vasodilation [4][5][6][7]. In addition, a common treatment for SCD, hydroxyurea (HU) stimulates production of Hb F and potentially leads to formation of NO.…”

Section: Introductionmentioning

confidence: 99%

The role of β93 Cys in the inhibition of Hb S fiber formation

Knee

Roden

Flory

et al. 2007

Biophysical Chemistry

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Recent studies have suggested that nitric oxide (NO) binding to hemoglobin (Hb) may lead to the inhibition of sickle cell fiber formation and the dissolution of sickle cell fibers. NO can react with Hb in at least 3 ways: 1) formation of Hb(II)NO, 2) formation of methemoglobin, and 3) formation of S-nitrosohemoglobin, through nitrosylation of the β93 Cys residue. In this study, the role of β93 Cys in the mechanism of sickle cell fiber inhibition is investigated through chemical modification with N-ethylmaleimide. UV resonance Raman, FT-IR and electrospray ionization mass spectroscopic methods in conjunction with equilibrium solubility and kinetic studies are used to characterize the effect of β93 Cys modification on Hb S fiber formation. Both FT-IR spectroscopy and electrospray mass spectrometry results demonstrate that modification can occur at both the β93 and α104 Cys residues under relatively mild reaction conditions. Equilibrium solubility measurements reveal that singlymodified Hb at the β93 position leads to increased amounts of fiber formation relative to unmodified or doubly-modified Hb S. Kinetic studies confirm that modification of only the β93 residue leads to a faster onset of polymerization. UV resonance Raman results indicate that modification of the α104 residue in addition to the β93 residue significantly perturbs the α 1 β 2 interface, while modification of only β93 does not. These results in conjunction with the equilibrium solubility and kinetic measurements are suggestive that modification of the α104 Cys residue and not the β93 Cys residue leads to T-state destabilization and inhibition of fiber formation. These findings have implications for understanding the mechanism of NO binding to Hb and NO inhibition of Hb S fiber formation.

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“…Secondly, S-NO bonds are exquisitely sensitive to tertiary and quaternary changes in protein structure, as well as to changes in cellular protein location [1,5,7,[16][17][18][19][20][21][22][23][24]. Modifications that are made between the time that the protein is being extracted from an intact cell and the time the S-NO bond is measured can dramatically affect results, particularly in the case of hemoglobin [18][19][20]24].…”

Section: Introductionmentioning

confidence: 99%

“…Modifications that are made between the time that the protein is being extracted from an intact cell and the time the S-NO bond is measured can dramatically affect results, particularly in the case of hemoglobin [18][19][20]24]. Therefore, a) preparations or assays that extensively modify protein chemistry as it relates to NO binding are likely to produce misleading results; b) in processing, relevant physiological parameters (such as pH and pO 2 ) of the cell matrix should be preserved as much as possible; c) each assay should be quantitatively validated with other assays in the biological range; and d) several additional steps -beyond simple assay -should be taken definitively to demonstrate that an S-NO modification of a specific cysteine results in a specific biological effect [2,19,23,24].…”

Section: Introductionmentioning

confidence: 99%

S-Nitrosothiol measurements in biological systems

Gow

Doctor

Mannick

et al. 2007

Journal of Chromatography B

107

116

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S-Nitrosothiol (SNO) cysteine modifications are regulated signaling reactions that dramatically affect, and are affected by, protein conformation. The lability of the S-NO bond can make SNOmodified proteins cumbersome to measure accurately. Here, we review methodologies for detecting SNO modifications in biology. There are three caveats. 1) Many assays for biological SNOs are used near the limit of detection: standard curves must be in the biologically relevant concentration range.2) The assays that are most reliable are those that modify SNO protein or peptide chemistry the least. 3) Each result should be quantitatively validated using more than one assay. Improved assays are needed and are in development.

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Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity

Cited by 111 publications

References 24 publications

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease

Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease

The role of β93 Cys in the inhibition of Hb S fiber formation

S-Nitrosothiol measurements in biological systems

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