Hemoglobin-Based Red Blood Cell Substitutes and Nitric Oxide

Yu, Binglan; Bloch, Kenneth D.; Zapol, Warren M.

doi:10.1016/j.tcm.2009.06.004

Cited by 36 publications

(29 citation statements)

References 30 publications

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“…Thus, although overall levels of SNO-Hb are unaltered, tissue perfusion and pO 2 are compromised in the absence of βCys93, indicating that the absence of βCys93 creates a deficit that is not compensated by either S-nitrosylation of an alternative site within the β-subunit or the presence of S-nitrosylated γCys93. Our data point to a major impairment in the autoregulation of blood flow, because tissue hypoxia normally is countered by increases in blood flow (hypoxic vasodilation) (7,(34)(35)(36). Indeed, impairments in oxygenation that accompany decreases in blood flow directly reflect diminished perfusion.…”

Section: Resultsmentioning

confidence: 71%

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Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Zhang

Hess

Qian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

112

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Oxygen delivery by Hb is essential for vertebrate life. Three amino acids in Hb are strictly conserved in all mammals and birds, but only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the β-chain (βCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO bioactivity by Hb redefines the respiratory cycle as a triune system (NO/O2/CO2). However, the physiological ramifications of RBC-mediated vasodilation are unknown, and the apparently essential nature of βCys93 remains unclear. Here we report that mice with a βCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia. In addition, βCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, βCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia.

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Section: Resultsmentioning

confidence: 71%

“…Indeed, impairments in oxygenation that accompany decreases in blood flow directly reflect diminished perfusion. [Of note, substitution of βCys93 results in only very minor increases in the O 2 -binding affinity of Hb (3,19) that would, if anything, conduce to increased blood flow (36).] Impaired Hypoxic Vasodilation in Vitro.…”

Section: Resultsmentioning

confidence: 99%

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Zhang

Hess

Qian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

112

View full text Add to dashboard Cite

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“…22 Mouse models given IV infusions of HBOC-201 demonstrate vasoconstriction via scavenging of endothelial NO (produced by NO synthase 3). 23 Thus depletion of NO may result in hypertension (due to systemic vasoconstriction) and increased risk for myocardial ischemia (related to coronary artery vasoconstriction). 5,6,24 A meta-analysis which included 3711 patients treated with HBOCs found a significantly increased risk of myocardial infarction associated with HBOC use (relative risk, 2.71; 95% CI, 1.67-4.40).…”

Section: Discussionmentioning

confidence: 99%

Difficult to swallow: warm autoimmune hemolytic anemia in a Jehovah's Witness treated with hemoglobin concentrate complicated by achalasia

et al. 2016

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“…There is currently no universal gauge that allows comparisons of levels of toxicity between various Hbcontaining solutions and whole blood (38,74,173,175). The deliberate introduction of acellular Hb into the bloodstream arose with the development of HBOCs.…”

Section: Microvascular Assessment Of Manifestation Of Toxicitymentioning

confidence: 99%

Examining and Mitigating Acellular Hemoglobin Vasoactivity

Cabrales

2013

Antioxidants & Redox Signaling

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Significance: There has been a striking advancement in our understanding of red cell substitutes over the past decade. Although regulatory oversight has influenced many aspects of product development in this period, those who have approached the demonstration of efficacy of red cell substitutes have failed to understand their implication at the level of the microcirculation, where blood interacts closely with tissue. Recent Advances: The understanding of the adverse effects of acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) has fortunately expanded from Hb-induced renal toxicity to a more complete list of biochemical mechanism. In addition, various unexpected adverse reactions were seen in early clinical studies. The effects of the presence of acellular Hb in plasma are relatively unique because of the convergence of mechanical and biochemical natures. Critical Issues: Controlling the variables using genetic engineering and chemical modification to change specific characteristics of the Hb molecule may allow for solving the complex multivariate problems of acellular Hb vasoactivity. HBOCs may never be rendered free of negative effects; however, quantifying the nature and extent of microvascular complications establishes a platform for designing new ameliorative therapies. Future Directions: It is time to leave behind the study of vasoactivity and toxicity based on bench-top measurements of biochemical changes and those based solely on systemic parameters in vivo, and move to a more holistic analysis of the mechanisms creating the problems, complemented with meaningful studies of efficacy. Antioxid. Redox Signal. 18, 2329-2341.

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Hemoglobin-Based Red Blood Cell Substitutes and Nitric Oxide

Cited by 36 publications

References 30 publications

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Difficult to swallow: warm autoimmune hemolytic anemia in a Jehovah's Witness treated with hemoglobin concentrate complicated by achalasia

Examining and Mitigating Acellular Hemoglobin Vasoactivity

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