Red blood cell regulation of microvascular tone  through adenosine triphosphate

Dietrich, Hans H.; Ellsworth, Mary L.; Sprague, Randy S.; Dacey, Ralph G.

doi:10.1152/ajpheart.2000.278.4.h1294

Cited by 230 publications

(236 citation statements)

References 26 publications

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“…Vasodilation (of aortic or pulmonary artery rings) by RBCs in bioassay is rapid, in keeping with the temporal requirements of arterial-venous transit (in seconds) (3,4). Moreover, when infused into animals, RBCs increase blood flow and improve oxygenation, an indication that RBCs elicit vasodilation in both the systemic and pulmonary circulations (1,(4)(5)(6). Collectively, the observation of vasoconstriction by RBCs at higher pO 2 but graded vasodilation with increasing hypoxia appears to provide a mechanism for matching blood flow to metabolic demand in the peripheral tissues and for matching ventilation to perfusion in the lungs (7).…”

mentioning

confidence: 74%

An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate

Angelo

Singel

Stamler³

2006

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

214

218

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Red blood cells (RBCs) act as O2-responsive transducers of vasodilator and vasoconstrictor activity in lungs and tissues by regulating the availability of nitric oxide (NO). Vasodilation by RBCs is impaired in diseases characterized by hypoxemia. We have proposed that the extent to which RBCs constrict vs. dilate vessels is, at least partly, controlled by a partitioning between NO bound to heme iron and to Cys␤93 thiol of hemoglobin (Hb). Hemes sequester NO, whereas thiols deploy NO bioactivity. In recent work, we have suggested that specific micropopulations of NO-liganded Hb could support the chemistry of S-nitrosohemoglobin (SNO-Hb) formation. Here, by using nitrite as the source of NO, we demonstrate that a (T state) micropopulation of a heme-NO species, with spectral and chemical properties of Fe(III)NO, acts as a precursor to SNO-Hb formation, accompanying the allosteric transition of Hb to the R state. We also show that at physiological concentrations of nitrite and deoxyHb, a S-nitrosothiol precursor is formed within seconds and produces SNO-Hb in high yield upon its prompt exposure to O 2 or CO. Deoxygenation͞reoxygenation cycling of oxyHb in the presence of physiological amounts of nitrite also efficiently produces SNO-Hb. In contrast, high amounts of nitrite or delays in reoxygenation inhibit the production of SNO-Hb. Collectively, our data provide evidence for a physiological S-nitrosothiol synthase activity of tetrameric Hb that depends on NO-Hb micropopulations and suggest that dysfunction of this activity may contribute to the pathophysiology of cardiopulmonary and blood disorders.hypoxic vasodilation ͉ nitric oxide ͉ S-nitrosohemoglobin ͉ S-nitrosylation H istorically, red blood cells (RBCs) have been regarded as transporters of oxygen (O 2 ) and carbon dioxide (CO 2 ), with the uptake of one and release of the other being reciprocally related. With the advent of the field of nitric oxide (NO) biology, RBCs also were thought to be scavengers of NO that could effectively quench its bioactivity. Some years ago, we noted that this limited view was inconsistent with the role of hemoglobin (Hb) in O 2 delivery, as sequestration of NO by Hb would lead to constriction of blood vessels, and this vasoconstriction, in turn, would limit the supply of O 2 (1). We subsequently demonstrated that vasoconstriction by RBCs is seen only at relatively high partial pressures of O 2 (pO 2 ); at lower pO 2 s characteristic of tissues (5-20 mm Hg), RBCs dilate blood vessels (2, 3). Vasodilation (of aortic or pulmonary artery rings) by RBCs in bioassay is rapid, in keeping with the temporal requirements of arterial-venous transit (in seconds) (3, 4). Moreover, when infused into animals, RBCs increase blood flow and improve oxygenation, an indication that RBCs elicit vasodilation in both the systemic and pulmonary circulations (1, 4-6). Collectively, the observation of vasoconstriction by RBCs at higher pO 2 but graded vasodilation with increasing hypoxia appears to provide a mechanism for matching blood flow to metaboli...

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mentioning

confidence: 74%

An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate

Angelo

Singel

Stamler³

2006

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

214

218

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“…Because it is Hb O 2 saturation, not the partial pressure of O 2 (pO 2 ), that is coupled to blood flow in vivo (1,3) it has been deduced that RBCs may serve as O 2 sensors within the integrated vascular system. In support of this idea, it has been shown recently that RBCs can act as O 2 -responsive transducers of vasodilator and vasoconstrictor activity (4)(5)(6)(7)(8)(9)(10), at least partly by modulating the availability of NO (6-8, 10, 11). According to these studies, RBCs release NO bioactivity under hypoxia and sequester it at hyperoxia.…”

Section: S-nitrosothiol (Sno)-deficient Rbcs Produce Impaired Vasodilmentioning

confidence: 93%

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

McMahon

Ahearn

Moya

et al. 2005

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

118

138

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The mechanism by which hypoxia [low partial pressure of O2 (pO2)] elicits signaling to regulate pulmonary arterial pressure is incompletely understood. We considered the possibility that, in addition to its effects on smooth muscle, hypoxia may influence pulmonary vascular tone through an effect on RBCs. We report that exposure of native RBCs to sustained hypoxia is accompanied by a buildup of heme iron-nitrosyl (FeNO) species that are deficient in pO 2-governed intramolecular transfer of NO to cysteine thiol, yielding a deficiency in the vasodilator S-nitrosohemoglobin (SNO-Hb). hemoglobin ͉ red blood cell vasodilation ͉ S-nitrosylation I n the systemic microcirculation, blood flow is regulated by physiological O 2 gradients that couple the O 2 content of blood to regulated vasodilation and vasoconstriction (1-3). Blood flow is thereby matched to tissue O 2 demand. An analogous mechanism operates in the lungs, where O 2 uptake (ventilation) is optimized through regulated vasodilation and vasoconstriction (perfusion). Blood flow is thereby matched to alveolar ventilation (2). Because it is Hb O 2 saturation, not the partial pressure of O 2 (pO 2 ), that is coupled to blood flow in vivo (1, 3) it has been deduced that RBCs may serve as O 2 sensors within the integrated vascular system. In support of this idea, it has been shown recently that RBCs can act as O 2 -responsive transducers of vasodilator and vasoconstrictor activity (4-10), at least partly by modulating the availability of [6][7][8]10,11). According to these studies, RBCs release NO bioactivity under hypoxia and sequester it at hyperoxia. The release of NO bioactivity would facilitate hypoxic vasodilation in peripheral tissues and oppose hypoxic pulmonary vasoconstriction (HPV) in the lungs. S-nitrosothiol (SNO)-deficientThe mechanism by which NO bioactivity escapes from RBCs is incompletely understood. It is generally accepted that the rapid reaction of NO with the hemes of Hb produces a heme-iron nitrosyl adduct (Hb [FeNO]) that exhibits no vasodilator activity (4,7,12). Hb also sustains S-nitrosylation at two cysteine residues conserved in all mammals and birds. Biochemical and mutational analyses (␤93Cys3Ala) indicate that S-nitrosohemoglobin (SNO-Hb) is formed upon oxygenation of Hb [FeNO] by means of heme-to-Cys NO transfer (13-15) and by transnitrosylative transfer from low-mass S-nitrosothiols (SNOs) (16,17). SNO-Hb is very stable in the oxygenated (or R) structure and thus cannot effectively dilate blood vessels (5, 10, 18). However, upon deoxygenation [or with change in the spin state of the hemes (3)], the vasodilator potency of SNO-Hb is markedly potentiated (5,16,18). Crystal structures and molecular models show that the ␤-Cys NO gains solvent access in the deoxygenated (or T) state (3, 19). Solvent-exposed NO can exchange with acceptor thiols within the N-terminal cytoplasmic domain of the RBC membrane anion exchange protein (AE1; band 3) (4, 15). Transnitrosylation of AE1 by SNO-Hb involves a direct protein-protein interaction. The st...

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“…Este proceso implica un control local del flujo, donde juegan un papel la inervación simpática perivascular, la cual influye en el tono arteriolar, la comunicación retrógrada a lo largo del endotelio la que es mediada por las células endoteliales y el rol de los eritrocitos como sensores intravasculares 27 .…”

Section: Mecanismos Involucrados En La Regulación De La Perfusión Micunclassified

La microcirculación en el paciente crítico: Parte I: generalidades y fisiología en el paciente séptico

et al. 2013

Rev. chil. pediatr.

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ARTÍCULO DE REVISIÓNREVIEW ARTICLE Rev Chil Pediatr 2013; 84 (1): 83-92 La microcirculación en el paciente crítico. ABSTRACT Microcirculation in the critically ill. Part I: Review and physiology of septic patientsSevere sepsis and septic shock involve circulatory, inflammatory and metabolic disorders eventually resulting in a disruption of cellular energy. Microcirculatory disturbances are common in septic patients. Microcirculation is the primary site of oxygen and nutrients exchange to cells. Direct observation using Sidestream Dark Field (SDF) imaging has allowed direct visualization of microcirculatory failure in critically ill patients. Septic shock is characterized by weak or vulnerable microcirculatory units and heterogeneity of microcirculatory flow. Multiple mechanisms may contribute to these alterations, including endothelial dysfunction, altered glycocalyx, impaired inter-cell communication and adhesion and rolling of white blood cells and platelets. Many therapeutic interventions routinely used in the treatment of critically ill patients seem to result in limited changes in microcirculatory perfusion, irrespective of systemic hemodynamics, due to the heterogeneous nature of these changes and the potentially involved mechanisms. Therefore, microcirculatory alterations and their presence in states of shock, especially in septic shock, can represent diagnostic and severity stratification tools and may be a target for therapeutic intervention (microcirculatory resuscitation), besides suggesting a prognostic role.

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Red blood cell regulation of microvascular tone through adenosine triphosphate

Cited by 230 publications

References 26 publications

An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate

An S -nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate

A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension

La microcirculación en el paciente crítico: Parte I: generalidades y fisiología en el paciente séptico

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