Article

The potential role of the red blood cell in nitrite-dependent regulation of blood flow

Department of Pathology and Center for Free Radical Biology, University of Alabama, Birmingham, AL 35294, USA.
Cardiovascular Research (Impact Factor: 5.81). 10/2010; 89(3):507-15. DOI: 10.1093/cvr/cvq323
Source: PubMed

ABSTRACT Nitrite was once thought to have little physiological relevance. However, nitrite is now being increasingly recognized as a therapeutic or possibly even physiological precursor of nitric oxide (NO) that is utilized when needed to increase blood flow. It is likely that different mechanisms for nitrite bioconversion occur in different tissues, but in the vascular system, there is evidence that erythrocyte haemoglobin (Hb) is responsible for the oxygen-dependent reduction of nitrite to modulate blood flow. Here, we review the complex chemical interactions of Hb and nitrite and discuss evidence supporting its role in vasodilation. We also discuss ongoing work focused on defining the precise mechanisms for export of NO activity from red blood cells and of other pathways that may mediate nitrite-dependent vasodilation.

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Available from: Rakesh P Patel, Feb 20, 2014
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    • "Therefore, alternative theories have been proposed that to explain enhanced NO production that incorporate the effect of lowering P O2 on the red blood cell, (i) ATP release in turn activating endothelial NOS production [7], (ii) NO release from S-nitrosohemoglobin [1], (iii) reduction of nitrite to NO [8] [9] [10]. The nitrite reductase mechanism has been proposed to involve deoxyhemoglobin acting as a reducing agent as shown in Eq. (1) [11] [12] [13] [14] [15]. "
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    ABSTRACT: The production of nitric oxide by hemoglobin (Hb) has been proposed to play a major role in the control of blood flow. Because of the allosteric nature of hemoglobin, the nitrite reductase activity is a complex function of oxygen partial pressure PO2. We have previous developed a model to obtain the micro rate constants for nitrite reduction by R state (kR) and T state (kT) hemoglobin in terms of the experimental maximal macro rate constant kNmax and the corresponding oxygen concentration PO2max. However, because of the intrinsic difficulty in obtaining accurate macro rate constant kN, from available experiments, we have developed an alternative method to determine the micro reaction rate constants (kR and kT) by fitting the simulated macro reaction rate curve (kN versus PO2) to the experimental data. We then use our model to analyze the effect of pH (Bohr Effect) and blood ageing on the nitrite reductase activity, showing that the fall of bisphosphoglycerate (BPG) during red cell storage leads to increase NO production. Our model can have useful predictive and explanatory power. For example, the previously described enhanced nitrite reductase activity of ovine fetal Hb, in comparison to the adult protein, may be understood in terms of a weaker interaction with BPG and an increase in the value of kT from 0.0087 M(-1)s(-1) to 0.083 M(-1)s(-1).
    Nitric Oxide 10/2013; 35. DOI:10.1016/j.niox.2013.10.007 · 3.18 Impact Factor
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    • "Herein we build upon the seminal findings that acute anemia causes a small (1–2%) but proportional and significant increase in MetHb in animal and human studies [2] [3]. Potential mechanisms for increased methemoglobin include: (1) direct oxidation of Hb to MetHb by NO or peroxides [22] [23]; (2) production of MetHb as an intermediate molecule in the biosynthesis of SNO-Hb [24]; and (3) as a product of deoxyhemoglobin (DeoxyHb) nitrite reductase activity [25]. Recently, a new mechanism has been described whereby MetHb can modulate NO signaling in the vascular compartment [26]. "
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    ABSTRACT: Acute anemia increases the risk for perioperative morbidity and mortality in critically ill patients who experience blood loss and fluid resuscitation (hemodilution). Animal models of acute anemia suggest that neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) is adaptive and protects against anemia-induced mortality. During acute anemia, we have observed a small but consistent increase in methemoglobin (MetHb) levels that is inversely proportional to the acute reduction in Hb observed during hemodilution in animals and humans. We hypothesize that this increase in MetHb may be a biomarker of anemia-induced tissue hypoxia. The increase in MetHb may occur by at least two mechanisms: (1) direct hemoglobin oxidation by increased nNOS-derived NO within the perivascular tissue and (2) by increased deoxyhemoglobin (DeoxyHb) nitrite reductase activity within the vascular compartment. Both mechanisms reflect a potential increase in NO signaling from the tissue and vascular compartments during anemia. These responses are thought to be adaptive; as deletion of nNOS results in increased mortality in a model of acute anemia. Finally, it is possible that prolonged activation of these mechanisms may lead to maladaptive changes in redox signaling. We hypothesize, increased MetHb in the vascular compartment during acute anemia may reflect activation of adaptive mechanisms which augment NO signaling. Understanding the link between anemia, MetHb and its treatments (transfusion of stored blood) may help us to develop novel treatment strategies to reduce the risk of anemia-induced morbidity and mortality.
    01/2013; 1(1):65-69. DOI:10.1016/j.redox.2012.12.003
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    • "The mechanisms by which hemoglobin deoxygenation is linked to activation of NO-signaling remain under investigation with three pathways receiving the most attention involving ATP release, S-nitrosohemoglobin (SNOHb) bioactivity and nitrite-reduction to NO [4] [6] [9] [21] [22] [23] [24]. The b93cys residue (b93cys) is conserved on hemoglobin in vertebrates but its function remains unclear. "
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    ABSTRACT: Two of the proposed mechanisms by which red blood cells (RBC) mediate hypoxic vasorelaxation by coupling hemoglobin deoxygenation to the activation of nitric oxide signaling involve ATP-release from RBC and S-nitrosohemoglobin (b93C(SNO)Hb) dependent bioactivity. However, different studies have reached opposite conclusions regarding the aforementioned mechanisms. Using isolated vessels, hypoxic vasorelaxation induced by human, C57BL/6 or mouse RBC which exclusively express either native human hemoglobin (HbC93) or human hemoglobin in which the conserved b93cys was replaced with Ala (HbC93A) were compared. All RBCs stimulated hypoxic vasodilation to similar extents suggesting the b93cys is not required for this RBC-mediated function. Hypoxic vasorelaxation was inhibited by co-incubation of ATP-pathway blockers including L-NAME (eNOS inhibitor) and Apyrase. Moreover, we tested if modulation of adenosine-dependent signaling affected RBC-dependent vasorelaxation using pan- or subtype specific adenosine receptor blockers, or adenosine deaminase (ADA). Interestingly, ADA and adenosine A2 receptor blockade, but not A1 receptor blockade, inhibited HbC93, HbC93A dependent hypoxic vasorelaxation. Equivalent results were obtained with human RBC. These data suggest that using isolated vessels, RBC do not require the presence of the b93cys to elicit hypoxic vasorelaxation and mediate this response via ATP- and a novel adenosine-dependent mechanism.
    International Journal of Physiology, Pathophysiology and Pharmacology 01/2013; 5(1):21-31.
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