Sexual Dimorphism in Whole Blood Nitrite and Susceptibility to Hypoxic Sickle Cell Vaso-Occlusive Injury in Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2327-2327
Author(s):  
Lewis L. Hsu ◽  
Andre Dejam ◽  
Mildred Pelletier ◽  
Audrey E. Cochard ◽  
Bhalchandra Diwan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sexual Dimorphism ◽  
Liver Injury ◽  
Sickle Cell ◽  
Whole Blood ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Hypoxic Exposure ◽  
No Bioavailability ◽  
Hypoxia Reoxygenation

Abstract Murine vasoregulation and ischemia-reperfusion injury studies indicate greater nitric oxide synthase (NOS) activity in females than in males, linked to estrogen upregulation of endothelial NOS-3 (eNOS). Plasma levels of nitrite ions have been used as an index of NOS activity in vivo. Our research on blood nitrite in humans indicates that eNOS-derived NO is stabilized as nitrite, transported by erythrocytes, and bioactivated by a nitrite reductase activity of deoxyhemoglobin (Dejam 2005 Blood 106:734–739). Transgenic mice expressing exclusively human sickle hemoglobin (sickle mice) originally from Berkeley (Pastzy, 1997) are susceptible to vaso-occlusive ischemic injury from hypoxia, and increased NO availability may protect against this ischemic injury. Hypothesis: Females will have higher whole blood nitrite levels, which will be a marker of NO bioavailability and protection against ischemic challenges such as sickle cell vaso-occlusive liver injury after hypoxia-reoxygenation. Methods: Whole blood samples were stabilized with a ferricyanide solution as previously described (Dejam 2005), then analyzed for nitrite levels using reductive chemiluminescence. C57BL6 mice were studied at baseline, during normobaric hypoxia (10% O2), or 1 hour after injection of the NOS inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO, 30 mg/kg) vs saline. Sickle mice had hypoxia-reoxygenation challenge to induce sickle vaso-occlusive injury: 2 hours of hypoxia followed by blood sample 18 hours later for serum alanine aminotransferase (ALT) as a marker of ischemic injury. Results: Average whole blood nitrite was 16% (SEM 7%) lower in males than in females, with much individual variation. Hypoxic exposure as short as 15 minutes lowered nitrite by 40% (SEM 7%). The magnitude of L-NIO effect was similar, lowering nitrite by 30% (SEM 9%). Female sickle mice and C57BL6 mice of both sexes showed no rise in ALT after hypoxia-reoxygenation, but male sickle mice showed 3-fold rise in ALT (p < 0.05). Ovariectomized female sickle mice had elevated ALT that was no different from males. Discussion: Murine whole blood nitrite levels show sexual dimorphism consistent with estrogen upregulation of eNOS. L-NIO inhibition of NOS was associated with a fall in nitrite level, consistent with inhibition of nitric oxide production. The remaining nitrite after NOS inhibition is likely to be controlled by the several eNOS-independent influences on nitrite, such as dietary nitrite and nitrate, and systemic inflammation. Although hypoxia was expected to upregulate eNOS production of NO, nitrite levels fell significantly with moderate hypoxia, consistent with reduction of nitrite to NO by deoxyhemoglobin. Male sickle mice and ovariectomized females are susceptible to liver injury with hypoxic-reoxygenation challenge, consistent with a role for female hormones in upregulating protective NO bioavailability. Thus, modest changes in NO bioavailability are potentially enough to protect against sickle cell vaso-occlusive injury. Future studies to correlate whole blood nitrite levels with vasoregulation and ischemic protection are feasible with this new method for experimental measurement of whole blood nitrite.

Low-dose ethanol attenuates gut ischemia/reperfusion-induced liver injury in rats via nitric oxide production

2003 ◽  
Vol 18 (2) ◽  
pp. 211-217 ◽  
Author(s):  
YOSHINORI HORIE ◽  
YOSHIYUKI YAMAGISHI ◽  
SHINZO KATO ◽  
MIKIO KAJIHARA ◽  
HIROYUKI KIMURA ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Liver Injury ◽  
Low Dose ◽  
Ischemia Reperfusion ◽  
Nitric Oxide Production ◽  
Oxide Production

Spontaneous Pulmonary Hypertension in Transgenic Sickle Cell Mice - Hemodynamics and Histology Suggest Abnormal Nitric Oxide Production and Scavenging.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 208-208
Author(s):  
Lewis L. Hsu ◽  
Hunter C. Champion ◽  
Elizabeth Manci ◽  
Bhalchandra Diwan ◽  
Daniel Schimel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Cardiac Catheterization ◽  
Sickle Cell ◽  
No Synthase ◽  
No Donor ◽  
Vascular Congestion ◽  
No Consumption ◽  
No Bioavailability

Abstract Pulmonary hypertension is increasingly recognized in sickle cell disease (SCD) as a strong risk factor for early mortality. The finding of pulmonary hypertension in other hemolytic anemias suggests that the mechanism is linked to hemolysis and/or thrombosis. Pathophysiologic roles of nitric oxide (NO) consumption and recurrent lung injury have been considered. Transgenic mice expressing exclusively human sickle hemoglobin (sickle mice)(Pastzy 1997) are well established models of severe hemolytic anemia and ischemic organ damage in SCD, and provide the opportunity to examine mechanisms of pulmonary hypertension with invasive studies. Hypotheses: Pulmonary hypertension will spontaneously occur in sickle mice but not age-matched colony controls, and severity will increase as the mice grow older. Methods: Male sickle mice were compared with age-matched hemizygotes from the same colony. Mice had cardiac catheterization for baseline hemodynamics, then challenges to assess pulmonary vascular responsiveness. A pathologist made blinded assessments of the pulmonary histology. Results: Cardiac catheterization showed pulmonary hypertension in all sickle mice, and blunted pulmonary vasodilation to all NO donor compounds as well as authentic NO gas. Computed tomography in vivo detected pulmonary vascular congestion. Older sickle mice had modestly increased vessel wall thickness and vascular congestion but no thrombi by histology. Older mice also appear to be in right heart failure. Sickle mouse lungs had decreased eNOS activity (measured by L-arginine to citrulline turnover) and loss of active eNOS dimer (measured by western blotting). Sickle mouse plasma had high NO consumption, consistent with increased NO scavenging by free hemoglobin released by steady state hemolysis. mean & SD hemizygote control (5 mo & 13 mo) 5 mo sickle 13 mo sickle Pulmonary Arterial Pressure (torr) 9.4 (0.7) 18.2 (0.5) 14.8 (0.3) Pulmonary Vascular Resistance 0.37 (0.6) 0.80 (0.07) 0.75 (0.04) Cardiac Output (ml/min) 14.2 (2) 17.1 (2) 12.2 (2) Vasodilation to NO & NO donors, or bradykinin (endothelium-dependent) normal blunted none Vasodilation to CGRP (NO-independent and endothelium-independent) normal normal blunted Hypoxic vasoconstriction (10%O2) normal enhanced enhanced Discussion: This is one of the few descriptions of spontaneous pulmonary hypertension in an animal, and implicates low NO bioavailability mediated by NO resistance/scavenging. Interestingly, pulmonary thromboembolism was not observed. Combined effects of NO scavenging and the loss of active eNOS dimer may explain paradoxical blunted responses to NO donor agents, blunted responses to NO synthase inhibition, and arginine supplementation observed in patients with SCD, despite increased NO synthase protein expression. It is also likely that aberrant superoxide formation from uncoupled monomeric NO synthase contributes to vascular NO scavenging. In conclusion, pulmonary hypertension, associated with a vasoconstrictor phenotype and low NO bioavailability, develops early in the sickle cell transgenic mouse.

Nitric Oxide Effects in Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-48-sci-48
Author(s):  
Lori Styles
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxidant Stress ◽  
Cell Disease ◽  
No Donors ◽  
Skin Ulcers ◽  
No Bioavailability ◽  
Inhaled No

Sickle cell disease (SCD) is a complex hemoglobinopathy characterized by microvascular occlusion and hemolytic anemia. Patients suffer from a myriad of both acute and chronic problems affecting virtually every organ system. Historically, microvascular occlusion has been the focus of scientific investigations into these manifestations and the chronic hemolysis of SCD was overlooked. More recently, however, the importance of the pathophysiology of hemolysis has been appreciated and related to a subset of the clinical manifestations of SCD, including pulmonary hypertension, priapism, skin ulcers, and possibly stroke. This subphenotype of SCD has been convincingly related to impaired nitric oxide (NO) homeostasis due to hemolysis. NO has pleiotropic effects including vaso-dilatory, antioxidative, anti-adhesion, and anti-thrombotic properties, which are all potentially important in the pathophysiology of SCD. Perturbation of NO homeostasis, therefore, could profoundly impact patients with SCD. Animal and human data support a state of “NO resistance” in SCD patients. Human studies have shown that SCD patients have a decreased response to exogenous NO donors and that is likely due to the scavenging of NO by free plasma hemoglobin that results from ongoing hemolysis. “NO resistance” is further augmented by the increased levels of reactive oxygen species (ROS) known to occur in SCD patients. High levels of ROS favor additional hemolysis through increased oxidant stress on the sickle red blood cell and reduce NO bioavailability by inactivation of circulating NO. With the substantial human and animal data to support a role for “NO resistance” in the pathophysiology of SCD, investigation with NO-based therapy have begun. Several approaches to overcoming “NO resistance” can be devised including increasing the precursors to NO, decreasing hemolysis, direct NO donors, and decreasing oxidant stress. To date, studies evaluating arginine (NO precursor), inhaled NO, and sildenafil (NO donor) have been reported. Oral arginine showed no benefit in a large clinical trial, and a preliminary trial of inhaled NO had only minimal benefit. Sildenafil may be more promising and is under further study. Lastly, although impaired NO bioavailability has been related to a subset of patients with pulmonary hypertension, skin ulcers and priapism, it will be important to determine what impact NO has on other manifestations, such as vaso-occlusive pain episodes and whether NO modulation can also be used therapeutically in this setting.

scholarly journals Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress

2008 ◽  
Vol 295 (1) ◽  
pp. H39-H47 ◽  
Author(s):  
Dhananjay K. Kaul ◽  
Xiaoqin Zhang ◽  
Trisha Dasgupta ◽  
Mary E. Fabry
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Reactivity ◽  
Microvascular Function ◽  
Cell Disease ◽  
No Bioavailability ◽  
Cox 2 ◽  
And Oxidative Stress

In sickle cell disease, nitric oxide (NO) depletion by cell-free plasma hemoglobin and/or oxygen radicals is associated with arginine deficiency, impaired NO bioavailability, and chronic oxidative stress. In transgenic-knockout sickle (BERK) mice that express exclusively human α- and βS-globins, reduced NO bioavailability is associated with induction of non-NO vasodilator enzyme, cyclooxygenase (COX)-2, and impaired NO-mediated vascular reactivity. We hypothesized that enhanced NO bioavailability in sickle mice will abate activity of non-NO vasodilators, improve vascular reactivity, decrease hemolysis, and reduce oxidative stress. Arginine treatment of BERK mice (5% arginine in mouse chow for 15 days) significantly reduced expression of non-NO vasodilators COX-2 and heme oxygenase-1. The decreased COX-2 expression resulted in reduced prostaglandin E2(PGE2) levels. The reduced expression of non-NO vasodilators was associated with significantly decreased arteriolar dilation and markedly improved NO-mediated vascular reactivity. Arginine markedly decreased hemolysis and oxidative stress and enhanced NO bioavailability. Importantly, arteriolar diameter response to a NO donor (sodium nitroprusside) was strongly correlated with hemolytic rate (and nitrotyrosine formation), suggesting that the improved microvascular function was a response to reduced hemolysis. These results provide a strong rationale for therapeutic use of arginine in sickle cell disease and other hemolytic diseases.

scholarly journals The Absence of Endothelial Sodium Channel α (αENaC) Reduces Renal Ischemia/Reperfusion Injury

2019 ◽  
Vol 20 (13) ◽  
pp. 3132 ◽  
Author(s):  
Antoine Tarjus ◽  
Cecilia González-Rivas ◽  
Isabel Amador-Martínez ◽  
Benjamin Bonnard ◽  
Rebeca López-Marure ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sodium Channel ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Cell Stiffness ◽  
Mrna Levels ◽  
Lipocalin 2 ◽  
Tubular Injury ◽  
No Bioavailability

The epithelial sodium channel (ENaC) has a key role in modulating endothelial cell stiffness and this in turn regulates nitric oxide (NO) synthesis. The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. Renal ischemia/reperfusion (IR) injury is characterized by vasoconstriction and sustained decrease in renal perfusion that is partially explained by a reduction in NO bioavailability. Therefore, we aimed to explore if an endothelial ENaC deficiency has an impact on the severity of renal injury induced by IR. Male mice with a specific endothelial sodium channel α (αENaC) subunit gene inactivation in the endothelium (endo-αENaCKO) and control littermates were subjected to bilateral renal ischemia of 22 min and were studied after 24 h of reperfusion. In control littermates, renal ischemia induced an increase in plasma creatinine and urea, augmented the kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin-2 (NGAL) mRNA levels, and produced severe tubular injury. The absence of endothelial αENaC expression prevented renal tubular injury and renal dysfunction. Moreover, endo-αENaCKO mice recovered faster from renal hypoxia after the ischemia episode as compared to littermates. In human endothelial cells, pharmacological ENaC inhibition promoted endothelial nitric oxide synthase (eNOS) coupling and activation. Altogether, these data suggest an important role for endothelial αENaC in kidney IR injury through improving eNOS activation and kidney perfusion, thus, preventing ischemic injury.

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 177-185 ◽  
Author(s):  
Claudia R. Morris
Keyword(s):  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion ◽  
Clinical Manifestations ◽  
Single Amino Acid ◽  
Common Denominator ◽  
Central Feature ◽  
Cell Disease ◽  
No Bioavailability

AbstractMany mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.

Inhibition of Increased Sickle Neutrophil Adhesion to Fibronectin and ICAM-1 by a Nitric Oxide Donor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3776-3776 ◽  
Author(s):  
Andreia A. Canalli ◽  
Nicola Conran ◽  
Sara T.O. Saad ◽  
Fernando F. Costa
Keyword(s):  
Nitric Oxide ◽  
Cell Adhesion ◽  
Sickle Cell ◽  
Leukocyte Adhesion ◽  
Second Messenger ◽  
Nitric Oxide Donor ◽  
Neutrophil Adhesion ◽  
Adhesive Properties ◽  
No Bioavailability ◽  
Nitric Oxide Metabolites

Abstract Leukocytes play an important role in sickle cell disease (SCD); increased numbers of leukocytes are associated with increased SCD morbidity and mortality and leukocytes participate significantly in the vaso-occlusive process. Nitric oxide (NO), a signaling gas involved in vaso-relaxation and platelet aggregation regulation, has recently been implicated as important in SCD pathophysiology. NO plasma bioavailability is thought to be decreased in SCD, and NO therapy has been proposed for SCD and vaso-occlusive crises treatment. The possible consequences of decreased NO bioavailability in SCD are innumerous and have yet to be fully explored. As NO is an important inflammatory mediator and may be important for the inhibition of leukocyte adhesion and migration mechanisms, we compared nitric oxide metabolites and cGMP levels (second messenger for NO) in neutrophils from normal subjects and SCD patients (SCD neutrophils) and then compared to the adhesive properties of these cells and observed the effect of NO donating agents on this adhesion. Neutrophils were isolated from whole blood by separating on a Ficoll gradient. NO metabolites/cGMP level were measured in neutrophil extracts using specific assays. Levels of nitric oxide metabolites in SCD neutrophils did not differ signicantly from those in normal neutrophils (17.34 ± 7.02%, n=10; 16.30 ± 7.00%, n=8; respectively). Furthermore, levels of cGMP (0.11 ± 0.02 pMol/1x107 neutrophils, n=9) in SCD neutrophils were not significantly different to those observed in normal neutrophils (0.142 ± 0.036 pMol/1x107 neutrophils, n=7; p>0.05). Cell adhesion to fibronectin and ICAM-1 was compared using static adhesion assays. Neutrophils from SCD patients demonstrated a significantly greater adhesion to FN-coated plates (FN= 20mg/ml) than normal neutrophils (18.73 ± 6.24%, n=18; 13.52 ± 5.15%, respectively, n=15; p=0.016). Similarly, neutrophils from SCD patients demonstrated significantly higher adhesion to ICAM-1 (10mg/ml) when compared to normal neutrophils (19.51 ± 9.02%, n=13; 10.98 ± 3.95%, respectively n=9; p=0.025). Co-incubation of SCD neutrophils with a nitric oxide donor, sodium nitroprusside (SNP,10mM) abolished their increased adhesion to both FN and ICAM-1 to levels similar to those of normal neutrophil adhesion (16.53 ± 2.27 %, reduced to 12.61 ± 1.98%, n=8; p= 0.002 for fibronectin and 19.12 ± 3.00% reduced to 16.49 ± 2.60, n=8; p=0.009 for ICAM-1). In contrast, SNP did not affect normal neutrophil adhesion to either FN (11.59 ± 1.02% and 12.67 ± 1.35%, following incubation n=11; p>0.05) or ICAM-1 (12.33 ± 0.25% to 11.95 ± 0.62%, n= 5; p> 0.05) significantly. Although NO bioavailability may be decreased in the plasma of SCD patients due to NO sequestration by cell-free hemoglobin, our data indicate that NO dynamics are not significantly altered in the leukocytes of patients in SCD, as indicated by levels of NO metabolites and the major second messenger for NO, cGMP, are not significantly different in sickle cell neutrophils. We speculate that increased neutrophil adhesive properties in SCD may not be the consequence of decreased NO bioavailability, rather, other factors such as altered cytokine levels may mediate increased cell adhesion. However, whilst increased adhesion appears not to be mediated by NO-dependent mechanisms, an NO donor significantly reduced increased SCD neutrophil adhesion to both FN and ICAM-1, indicating that NO and NO donating drugs may also benefit SCD patients by reducing increased leukocyte adhesion, a mechanism important for the vaso-occlusive process.

Atorvastatin Therapy Restores Nitric Oxide-Dependent Vascular Responsiveness in Patients with Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 239-239 ◽  
Author(s):  
Gregory J. Kato ◽  
Christian Hunter ◽  
Lori Hunter ◽  
Andre Dejam ◽  
Roberto Machado ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cell Adhesion ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxidant Stress ◽  
Cell Disease ◽  
Atorvastatin Therapy ◽  
Vascular Responsiveness ◽  
No Bioavailability

Abstract We and others have published biochemical and physiological evidence supporting a model in which intravascular hemolysis and oxidant stress in patients with sickle cell disease (SCD) results in impaired nitric oxide (NO) bioavailability, with an associated reduction in NO-dependent blood flow. This reduced bioavailability is characterized by NO destruction and thus a resistance to both endogenous and exogenous (nitroprusside, nitroglycerin, NONOates) NO. A crucial regulator of endothelial cell homeostasis, NO regulates basal vasodilation, inhibits platelet aggregation, and tonically inhibits expression of cell adhesion molecules by endothelial cells, including vascular cell adhesion molecule (VCAM-1). Statins have been reported to both improve NO-dependent blood flow and reduce oxidant stress in patients with hypercholesterolemia and in normal subjects. We therefore investigated whether atorvastatin has similar effects in patients with SCD. Five patients have completed the study (targeted enrollment will be 15 patients); patients were selected for suspected NO-dependent vascular dysfunction as determined by higher than median plasma levels of soluble VCAM-1 or pulmonary hypertension (tricuspid regurgitant jet velocity > 2.4 meters/second). Baseline vascular reactivity to arterial infusions of sodium nitroprusside (SNP), acetylcholine (ACh), and the inhibitor of endothelial NO synthesis, L-NG-monomethyl-L-arginine (L-NMMA) at increasing doses was assessed by forearm venous occlusion plethysmography. Patients took atorvastatin 10 mg daily for two weeks, then 20 mg daily for another two weeks, and forearm studies were repeated. All patients tolerated the drug without adverse effects. Plasma total cholesterol levels decreased in all patients, (baseline 115 ± 5 mg/dL, post-treatment 93 ± 5 mg/dL (mean ± SEM), p=0.002). Serum creatine kinase increased slightly, but remained in the normal range (55 ± 9 vs. 73 ± 18 IU/L, p=0.15). All patients had markedly impaired responses at baseline to SNP, ACh and L-NMMA compared to healthy control subjects, validating our screening methodology to identify subjects with NO resistance. After four weeks of oral atorvastatin therapy, responsiveness to both SNP and ACh significantly improved in each group compared to baseline by ANOVA with repeated measures (p < 0.05). Response to L-NMMA was not significantly affected. These data provide a non-invasive strategy for identifying patients with NO-resistance (endothelial dysfunction) by screening soluble VCAM-1 levels and tricuspid regurgitant jet velocities, and further suggest that high pulmonary artery systolic pressures in this population are associated with reduced NO bioavailability. Additionally, we show that short term use of the FDA approved medication atorvastatin, is safe in this population. Our data are consistent with statin-mediated improvement in vascular responsiveness to NO that is independent of improved endothelial NO production, and support consideration of statins in clinical trials to reduce vascular occlusion in patients with SCD. Figure Figure

Potential of Angeli’s Salt To Reduce Nitric Oxide Scavenging in Hemolysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3788-3788
Author(s):  
Daniel B. Kim-Shapiro ◽  
Xiaojun He ◽  
Ivan Azarov ◽  
Jodi Richardson ◽  
S. Bruce King ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sickle Cell ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Angeli's Salt ◽  
Iron Nitrosyl ◽  
Sickle Cell Crisis ◽  
No Bioavailability ◽  
Nitrosyl Hemoglobin

Abstract Since cell-free hemoglobin (Hb) scavenges nitric oxide (NO) more effectively than that encapsulated in the red blood cell (RBC), hemolysis reduces NO bioavailability with pathological consequences in sickle cell disease and other hemolytic anemias, paroxysmal nocturnal hemoglobinuria, thalassemia intermedia, malaria, and cardiopulomonary bypass. The ability of the cell-free Hb to scavenge NO is reduced when the Hb is converted from its oxygenated form (HbO2) to its oxidized form, methemoglobin (MetHb). We show that Angeli’s salt (AS) can convert two OxyHb to two MetHb molecules through its release of nitroxyl (HNO). AS also further converts the MetHb to less potentially oxidative forms: nitrite bound MetHb and iron-nitrosyl hemoglobin. We also show that, due to the fast reactivity of HNO with Hb (like NO), AS preferentially reacts with cell-free rather than RBC encapsulated Hb. In conditions simulating sickle cell crisis, within six minutes, AS converted 45 ± 12% of cell-free Hb to non-NO scavenging forms (MetHb and iron-nitrosyl Hb) and only converted 0.4 ± 0.3% of RBC encapsulated Hb (n=3). Similar preferential reactivity was observed under other physiologically relevant conditions. We conclude that, as AS preferentially reacts with cell-free Hb compared to RBC encapsulated Hb, converting it to species that do not effectively scavenge NO, it is has promise as a treatment for increasing NO biavailability in conditions associated with hemolysis.

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