How do red blood cells cause hypoxic vasodilation? The SNO-hemoglobin paradigm.

One of the most intriguing areas of research in erythrocyte physiology is the interaction of hemoglobin with nitric oxide (NO). These two molecules independently fulfill diverse and complex physiological roles, while together they subtly modulate microvascular perfusion in response to second-by-second changes in local metabolic demand, contributing to hypoxic vasodilation. It is through an appreciation of the temporal and structural constraints of the microcirculation that the principal requirements of the physiological interplay between NO and hemoglobin are revealed, elucidating the role of the erythrocyte in hypoxic vasodilation. Among the candidate molecular mechanisms, only S-nitrosohemoglobin (SNO-hemoglobin) directly fulfills the physiological requirements. Thus, NO is transported by red blood cells to microvascular sites of action in protected form as an S-nitrosothiol on the highly conserved hemoglobin beta-93 Cys residue, invariant in birds and mammals. SNO-hemoglobin dispenses NO bioactivity to microvascular cells on the release of oxygen, physiologically coupling hemoglobin deoxygenation to vasodilation. SNO-hemoglobin is the archetype for the role of S-nitrosylation in a newly identified class of biological signals, and disturbances in SNO-hemoglobin activity are associated with the pathogenesis of several important vascular diseases.

[1]  J. Stamler,et al.  S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control , 1996, Nature.

[2]  Michael Angelo,et al.  An S-nitrosothiol (SNO) synthase function of hemoglobin that utilizes nitrite as a substrate. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Kubes,et al.  Enhanced S-Nitroso-Albumin Formation From Inhaled NO During Ischemia/Reperfusion , 2004, Circulation research.

[4]  R. Woodson,et al.  Effect of increased oxygen affinity and anemia on cardiac output and its distribution. , 1982, Journal of applied physiology: respiratory, environmental and exercise physiology.

[5]  A. Popel,et al.  Venular endothelium-derived NO can affect paired arteriole: a computational model. , 2006, American journal of physiology. Heart and circulatory physiology.

[6]  J. Stamler,et al.  Routes to S-nitroso-hemoglobin formation with heme redox and preferential reactivity in the β subunits , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Saltin,et al.  Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery: Role of Circulating ATP , 2002, Circulation research.

[8]  J. Lancaster,et al.  Hemoglobin-mediated, hypoxia-induced vasodilation via nitric oxide: mechanism(s) and physiologic versus pathophysiologic relevance. , 2005, American journal of respiratory cell and molecular biology.

[9]  J. H. Comroe,et al.  THE RATE OF UPTAKE OF CARBON MONOXIDE AND OF NITRIC OXIDE BY NORMAL HUMAN ERYTHROCYTES AND EXPERIMENTALLY PRODUCED SPHEROCYTES , 1958, The Journal of general physiology.

[10]  E. Funai,et al.  S-nitrosohemoglobin in the fetal circulation may represent a cycle for blood pressure regulation. , 1997, Biochemical and biophysical research communications.

[11]  Santiago Lamas,et al.  Nitrosylation The Prototypic Redox-Based Signaling Mechanism , 2001, Cell.

[12]  F. Roughton,et al.  The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin , 1957, The Journal of physiology.

[13]  Robert N. Taylor,et al.  S-Nitrosoalbumin–Mediated Relaxation Is Enhanced by Ascorbate and Copper: Effects in Pregnancy and Preeclampsia Plasma , 2005, Hypertension.

[14]  M. Frenneaux,et al.  Vasorelaxation by Red Blood Cells and Impairment in Diabetes: Reduced Nitric Oxide and Oxygen Delivery by Glycated Hemoglobin , 2004, Circulation research.

[15]  S. Herold,et al.  Reactions of Deoxy-, Oxy-, and Methemoglobin with Nitrogen Monoxide , 2003, Journal of Biological Chemistry.

[16]  M. Frenneaux,et al.  Red Blood Cell Nitric Oxide as an Endocrine Vasoregulator: A Potential Role in Congestive Heart Failure , 2004, Circulation.

[17]  D. Abernethy,et al.  Active Nitric Oxide Produced in the Red Cell under Hypoxic Conditions by Deoxyhemoglobin-mediated Nitrite Reduction* , 2003, Journal of Biological Chemistry.

[18]  J. Stamler,et al.  Export by red blood cells of nitric oxide bioactivity , 2001, Nature.

[19]  Zhi Huang,et al.  Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. , 2006, Blood.

[20]  J. Stamler,et al.  A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Stamler,et al.  Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. , 1993, The Journal of clinical investigation.

[22]  M. Gladwin,et al.  Nitric oxide's reactions with hemoglobin: a view through the SNO-storm , 2003, Nature Medicine.

[23]  J. Stamler,et al.  S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Cain,et al.  Raising P50 increases tissue PO2 in canine skeletal muscle but does not affect critical O2 extraction ratio. , 1997, Journal of applied physiology.

[25]  D. Gozal,et al.  S-Nitrosothiols signal the ventilatory response to hypoxia , 2001, Nature.

[26]  B. Piknova,et al.  Transduction of NO-bioactivity by the red blood cell in sepsis: novel mechanisms of vasodilation during acute inflammatory disease. , 2004, Blood.

[27]  Ewald R. Weibel,et al.  The pathway for oxygen : structure and function in the mammalian respiratory system , 1984 .

[28]  I. T. Demchenko,et al.  Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. , 1997, Science.

[29]  David J Singel,et al.  Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. , 2005, Annual review of physiology.

[30]  M. Gladwin,et al.  Biological activity of nitric oxide in the plasmatic compartment. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  T. McMahon,et al.  Hemoglobin conformation couples erythrocyte S-nitrosothiol content to O2 gradients. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Gladwin,et al.  Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator , 2004, Nature Medicine.

[33]  M. Frenneaux,et al.  Detection of Human Red Blood Cell-bound Nitric Oxide* , 2005, Journal of Biological Chemistry.

[34]  J. Liao,et al.  Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  S. Basu,et al.  Lack of allosterically controlled intramolecular transfer of nitric oxide from the heme to cysteine in the beta subunit of hemoglobin. , 2006, Blood.

[36]  M. Gladwin,et al.  Erythrocytes are the major intravascular storage sites of nitrite in human blood. , 2005, Blood.

[37]  W. Sibbald,et al.  Increasing P(50) does not improve DO(2CRIT) or systemic VO(2) in severe anemia. , 2002, American journal of physiology. Heart and circulatory physiology.

[38]  J. Stamler,et al.  Nitric oxide in the human respiratory cycle , 2002, Nature Medicine.

[39]  N. Gorbunov,et al.  Brisk production of nitric oxide and associated formation of S-nitrosothiols in early hemorrhage. , 2006, Journal of applied physiology.

[40]  P. Low,et al.  Heme Redox Properties of S-Nitrosated Hemoglobin A0 and Hemoglobin S , 2002, The Journal of Biological Chemistry.

[41]  M. Gladwin,et al.  Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation , 2003, Nature Medicine.