Thromb Haemost 2007; 98(05): 970-974
DOI: 10.1160/TH07-04-0305
Theme Issue Article
Schattauer GmbH

New functional aspects of the L-arginine-nitric oxide metabolism within the circulating blood

Petra Kleinbongard
1   Department of Medicine, Medical Clinic I, University Hospital RTWH Aachen, Germany
,
Stefanie Keymel
1   Department of Medicine, Medical Clinic I, University Hospital RTWH Aachen, Germany
,
Malte Kelm
1   Department of Medicine, Medical Clinic I, University Hospital RTWH Aachen, Germany
› Author Affiliations
Further Information

Publication History

Received 25 April 2007

Accepted after resubmission 03 October 2007

Publication Date:
30 November 2017 (online)

Summary

Nitric oxide (NO) is a signaling molecule of major importance modulating not only the function of the vascular wall but also that of blood cells, such as platelets and leukocytes. The synthesis of NO in the circulation has been attributed mainly to the vascular endothelium. Red blood cells (RBC) have been demonstrated to carry a non-functional NOS and – due to their huge haemoglobin content – have been assumed to metabolize large quantities of NO. More recently, however, RBC have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We provide evidence that RBC from humans express an active and functional endothelial type NOS. RBC NOS activity may regulate deformability of RBC, and inhibits activation of platelets. This review aims to discuss the potential role of RBC NOS in the circulation and new concepts of NO research in the microcirculation.

 
  • References

  • 1 Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002-2012.
  • 2 Palmer RMJ, Ferrige AG, Moncada S. et al. Nitric oxide release accounts for the biological activity of endothelium- derived relaxing factor. Nature 1987; 327: 524-526.
  • 3 Rassaf T, Kleinbongard P, Preik M. et al. Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: experimental and clinical study on the fate of NO in human blood. Circ Res 2002; 91: 470-477.
  • 4 Ignarro LJ. Biosynthesis and metabolism of endothelium- derived nitric oxide. Annu Rev Pharmacol Toxicol 1990; 30: 535-560.
  • 5 Celermajer DS, Sorensen KE, Bull C. et al. Endothelium- dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 1994; 24: 1468-1474.
  • 6 Joannides R, Haefeli WE, Linder L. et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995; 91: 1314-1319.
  • 7 Bundgaard M. Functional implications of structural differences between consecutive segments of microvascular endothelium. Microcirc Endothelium Lymphatics 1988; 4: 113-142.
  • 8 Shimokawa H, Yasutake H, Fujii K. et al. The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol 1996; 28: 703-711.
  • 9 Pohl U, de Wit C. A unique role of NO in the control of blood flow. News Physiol Sci 1999; 14: 74-80.
  • 10 Doyle MP, Hoekstra JW. Oxidation of nitrogen oxides by bound dioxygen in haemoproteins. J Inorg Biochem 1981; 14: 351-358.
  • 11 McMahon TJ, Moon RE, Luschinger BP. et al. Nitric oxide in the human respiratory cycle. Nat Med 2002; 8: 711-717.
  • 12 Lancaster jr. JR. A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide 1997; 1: 18-30.
  • 13 Joshi MS, Ferguson TB, Han TH. et al. Nitric oxide is consumed, rather than conserved, by reaction with oxyhaemoglobin under physiological conditions. Proc Natl Acad Sci USA 2002; 99: 10341-10346.
  • 14 Liao JC, Hein TW, Vaughn MW. et al. Intravascular flow decreases erythrocyte consumption of nitric oxide. Proc Natl Acad Sci USA 1999; 96: 8757-8761.
  • 15 Liu X, Miller MJ, Joshi MS. et al. Diffusion-limited reaction of free nitric oxide with erythrocytes. J Biol Chem 1998; 273: 18709-18713.
  • 16 Vaughn MW, Huang KT, Kuo L. et al. Erythrocytes possess an intrinsic barrier to nitric oxide consumption. J Biol Chem 2000; 275: 2342-2348.
  • 17 Feelisch M, Rassaf T, Mnaimneh S. et al. Concomitant S-, N-, and heme-nitros(yl)ation in biological tissues and fluids: implications for the fate of NO in vivo. FASEB J 2002; 16: 1775-1785.
  • 18 Rassaf T, Bryan NS, Kelm M. et al. Concomitant presence of N-nitroso and S-nitroso proteins in human plasma. Free Radic Biol Med 2002; 33: 1590-1596.
  • 19 Kleinbongard P, Rassaf T, Dejam A. et al. Griess method for nitrite measurement of aqueous and protein containing sample. Methods Enzymol 2002; 359: 158-168.
  • 20 Kleinbongard P, Dejam A, Lauer T. et al. Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 2003; 35: 790-796.
  • 21 Grau M, Hendgen-Cotta U, Brouzos P. et al. Recent methodological advances in the analysis of nitrite in the human circulation: Nitrite as a biochemical parameter of the L-arginine/NO pathway. Journal of Chromatography B 2007; 851: 106-123.
  • 22 Lauer T, Preik M, Rassaf T. et al. Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proc Natl Acad Sci USA 2001; 98: 12814-12819.
  • 23 Kleinbongard P, Dejam A, Lauer T. et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 2006; 40: 295-302.
  • 24 Wennmalm A, Benthin G, Edlund A. et al. Metabolism and excretion of nitric oxide in humans. An experimental and clinical study. Circ Res 1993; 73: 1121-1127.
  • 25 Stamler JS, Jia L, Eu JP. et al. Blood flow regulation by S-nitrosohaemoglobin in the physiological oxygen gradient. Science 1997; 276: 2034-2037.
  • 26 McMahon TJ, Stone AE, Bonaventura J. et al. Functional coupling of oxygen binding and vasoactivity in S-nitrosohaemoglobin. J Biol Chem 2000; 275: 16738-16745.
  • 27 Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells. Annu Rev Physiol 2005; 67: 99-145.
  • 28 Hare JM, Stamler J. NO / redox disequilibrium in the failing heart and cardiovascular system. The Journal of Clinical Investigation 2005; 115: 509-517.
  • 29 Gladwin MT, Crawford JH, Patel RP. et al. The biochemistry of nitric oxide, nitrite, and haemoglobin: role in blood flow regulation. Free Radic Biol Med 2004; 36: 707-717.
  • 30 Cosby K, Partovi KS, Crawford JH. et al. Nitrite reduction to nitric oxide by deoxyhaemoglobin vasodilates the human circulation. Nat Med 2003; 9: 1498-1505.
  • 31 Gladwin MT. Nitrite as an intrinsic signaling molecule. Nature Chemical Biology 2005; 1: 245-246.
  • 32 Dejam A, Hunter CJ, Schechter AN. et al. Emerging role of nitrite in human biology. Blood Cells Mol Dis 2004; 32: 423-429.
  • 33 Gladwin MT, Raat N, Shiva S. et al. Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 2006; 291: H2026-H2035.
  • 34 Kim-Shapiro D, Schechter AN, Gladwin MT. et al. Unraveling the reactions of nitric oxide, nitrite, and haemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol 2006; 26: 697-705.
  • 35 Freedman JE, Sauter R, Battinelli EM. et al. Deficient platelet-derived nitric oxide and enhanced haemostasis in mice lacking the NOSIII gene. Circ Res 1999; 84: 1416-1421.
  • 36 Radomski MW, Palmer RM, Moncada S. et al. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987; 7: 1057-1058.
  • 37 Deliconstantinos G, Villiotou V, Stavrides JC. et al. Nitric oxide and peroxynitrite production by human erythrocytes: a causative factor of toxic anemia in breast cancer patients. Anticancer Res 1995; 15: 1435-1446.
  • 38 Jubelin BC, Gierman JL. Erythrocytes may synthesize their own nitric oxide. Am J Hypertens 1996; 9: 1214-1219.
  • 39 Chen LY, Mehta JL. Evidence for the presence of L-arginine-nitric oxide pathway in human red blood cells: relevance in the effects of red blood cells on platelet function. J Cardiovasc Pharmacol 1998; 32: 57-61.
  • 40 Ghigo D, Todde R, Ginsburg H. et al. Erythrocyte stages of Plasmodium falciparum exhibit a high nitric oxide synthase (NOS) activity and release an NOS-inducing soluble factor. J Exp Med 1995; 182: 677-688.
  • 41 Kang ES, Ford K, Grokulsky G. et al. Normal circulating adult human red blood cells contain inactive NOS proteins. J Lab Clin Med 2000; 135: 444-451.
  • 42 Metha JL, Metha P, Li D. et al. Nitric oxide synthase in adult red blood cells: vestige of an earlier age or a biologically active enzyme?. J Lab Clin Med 2000; 135: 430-431.
  • 43 Kleinbongard P, Schulz R, Rassaf T. et al. Red blood cells express a functional endothelial nitric oxide synthase. Blood 2006; 107: 2943-2951.
  • 44 Pawloski JR, Hess DT, Stamler JS. et al. Export by red blood cells of nitric oxide bioactivity. Nature 2001; 409: 622-626.
  • 45 Deem S, Kim SS, Min J-H. et al. Pulmonary vascular effects of red blood cells containing S-nitrosated haemoglobin. Am J Physiol Heart Circ Physiol 2004; 287: H2561-H2568.
  • 46 Liu L, Yan Y, Zeng M. et al. Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell 2004; 116: 617-628.
  • 47 Baker PRS, Schopfer FJ, Sweeney S. et al. Red cell membrane and plasma linoleic acid nitration products: synthesis, clinical identification, and quantification. Proc Natl Acad Sci USA 2005; 101: 11577-11582.
  • 48 Huang KT, Huang Z, Kim-Shapiro DB. et al. Nitric oxide red blood cell membrane permeability at high and low oxygen tension. Nitric Oxide 2007; 16: 209-216.
  • 49 De Rosa MC, Carelli Alinovi C, Galtieri A. et al. The plasma membrane of erythrocytes plays a fundamental role in the transport of oxygen, carbon dioxide and nitric oxide and in the maintenance of the reduced state of the heme iron. Gene 2007; 398: 162-171.
  • 50 Özüyaman B, Godecke A, Kusters S. et al. Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation. Thromb Haemost 2005; 93: 1161-1167.
  • 51 Rassaf T, Flögel U, Drexhage C. et al. Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ Res 2007; 100: 1749-1754.
  • 52 Shiva S, Huang Z, Grubina R. et al. Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res 2007; 100: 654-661.
  • 53 Teichert A-M, Miller TL, Tai SC. et al. In vivo expression profile of an endothelial nitric oxide synthase promoter-reporter transgene. Am J Physiol Heart Circ Physiol 2000; 278: H1352-H1361.
  • 54 Levy BI, Ambrosio G, Pries AR. et al. Microcirculation in hypertension. A new target for treatment? Circulation 2001; 104: 735-740.
  • 55 Struijker-Boudier HAJ, le Noble JL, Messing MW. et al. The microcirculation and hypertension. J Hypertens Suppl 1992; 10: S147-S156.
  • 56 Bor-Kucukatay M, Wenby RB, Meiselman HJ. et al. Effects of nitric oxide on red blood cell deformability. Am J Physiol Heart Circ Physiol 2003; 284: H1577-H1584.
  • 57 Radomski MW, Palmer RM, Moncada S. et al. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990; 87: 5193-5197.
  • 58 Cha YJ, Chang EA, Kim CH. et al. Effects of endothelial cells and mononuclear leukocytes on platelet aggregation. Haematologia (Budap) 2000; 30: 97-106.
  • 59 Baskurt OK, Gelmont D, Meiselman HJ. et al. Red blood cell deformability in sepsis. Am J Respir Crit Care Med 1998; 157: 421-427.
  • 60 Bateman RM, Jagger JE, Sharpe MD. et al. Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis. Am J Physiol Heart Circ Physiol 2001; 280: H2848-H2856.
  • 61 Bor-Kucukatay M, Meiselman HJ, Baskurt OK. et al. Modulation of density-fractionated RBC deformabilityby nitric oxide. Clin Haemorheol Microcirc 2005; 33: 363-367.
  • 62 Reid HL, Barnes AJ, Lock PJ. et al. Technical methods. A simple method for measuring erythrocyte deformability. J Clin Path 1976; 29: 855-858.
  • 63 Dobbe JG, Streekstra GJ, Hardeman MR. et al. Measurement of the distribution of red blood cell deformability using an automated rheoscope. Cytometry 2002; 50: 313-325.
  • 64 Artmann GM, Paul Sung K-L, Horn T. et al. Micropipette Aspiration of Human Erythrocytes Induces Echinocytes via Membrane Phospholipid Translocation. Biophys J 1997; 72: 1434-1441.
  • 65 Kensey KR. The mechanistic relationships between haemorheological characteristics and cardiovascular disease. Curr Med Res Opin 2003; 19: 587-596.
  • 66 Le Devehat C, Khodabandehlou T, Vimeux M. et al. Impaired haemorheological properties in diabetic patients with lower limb arterial ischaemia. Clin Haemorheol Microcirc 2001; 25: 43-48.
  • 67 Mchedlishvili G, Varazashvili M, Gobejishvili L. et al. Local RBC aggregation disturbing blood fluidity and causing stasis in microvessels. Clin Haemorheol Microcirc 2002; 26: 99-106.
  • 68 Ruschitzka FT, Wenger RH, Stallmach T. et al. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci USA 2000; 97: 11609-11613.
  • 69 Weiner DL, Hibberd PL, Betit P. et al. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. J Am Med Assoc 2003; 289: 1136-1142.
  • 70 Morris CR, Kuypers FA, Larkin S. et al. Arginine therapy: a novel strategy to induce nitric oxide production in sickle cell disease. Br J Haematol 2000; 111: 498-500.
  • 71 Serirom S, Raharjo WH, Chotivanich K. et al. Antiadhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am J Pathol 2003; 162: 1651-1660.