Abstract
Nitric oxide (NO) is inactivated in sickle cell disease (SCD), while bioavailability of arginine, the substrate for NO synthesis, is diminished. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a key factor in the pathophysiology of SCD. Inactivation of NO correlates with the hemolytic rate and is associated with erythrocyte release of cell-free hemoglobin and arginase during hemolysis. Accelerated consumption of NO is enhanced further by the inflammatory environment of oxidative stress that exists in SCD. Based upon its critical role in mediating vasodilation and cell growth, decreased NO bioavailability has also been implicated in the pathogenesis of pulmonary arterial hypertension (PHT). Secondary PHT is a common life-threatening complication of SCD that also occurs in most hereditary and chronic hemolytic disorders. Aberrant arginine metabolism contributes to endothelial dysfunction and PHT in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and PHT. Decompart-mentalization of hemoglobin into plasma consumes endothelial NO and thus drives a metabolic requirement for arginine, whose bioavailability is further limited by arginase activity. New treatments aimed at maximizing both arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, or oral arginine supplementation may represent novel therapeutic strategies.
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References
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337(11): 762–9
Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004; 364(9442): 1343–60
Castro O, Hoque M, Brown M. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2003; 101: 1257–61
Gladwin M, Sachdev V, Jison M, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004; 350: 22–31
Sutton LL, Castro O, Cross DJ, et al. Pulmonary hypertension in sickle cell disease. Am J Cardiol 1994; 74: 626–8
Ataga KI, Sood N, De Gent G, et al. Pulmonary hypertension in sickle cell disease. Am J Med 2004; 117: 665–9
Morris CR, Kato GJ, Poljakovic M, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension and mortality in sickle cell disease. JAMA 2005 Jul 6; 294(1): 81–90
Vichinsky EP. Pulmonary hypertension in sickle cell disease: a time for intervention. N Engl J Med 2004; 350: 857–9
Morris CR, Gardner J, Hagar W, et al. Pulmonary hypertension in sickle cell disease: a common complication for both adults and children [abstract no. 1666]. Blood 2004; 104: 463a
Hebbel RP, Osarogiagbon KD. The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy. Microcirculation 2004; 11: 129–51
Frenette PS. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol 2002; 9(2): 101–6
Parise LV, Telen MJ. Erythrocyte adhesion in sickle cell disease. Curr Hematol Rep 2003; 2(2): 102–8
Voetsch B, Jin RC, Loscalzo J. Nitric oxide insufficiency and atherothrombosis. Histochem Cell Biol 2004; 122(4): 353–67
Jison ML, Gladwin MT. Hemolytic anemia-associated pulmonary hypertension of sickle cell disease and the nitric oxide/arginine pathway. Am J Respir Crit Care Med 2003; 168: 3–4
Rother RP, Bell L, Hillmen P, et al. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 293: 1653–62
Morris C, Kuypers F, Kato G, et al. Hemolysis-associated pulmonary hypertension in thalassemia. Ann N Y Acad Sci 2005; 1054: 481–5
Lin EE, Rodgers GP, Gladwin MT. Hemolytic anemia-associated pulmonary hypertension in sickle cell disease. Curr Hematol Rep 2005; 4(2): 117–25
Reiter C, Wang X, Tanus-Santos J, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle cell disease. Nat Med 2002; 8: 1383–9
Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336: 111–7
Loscalzo J. Genetic clues to the cause of primary pulmonary hypertension. N Engl J Med 2001; 345: 367–71
Moraes D, Loscalzo J. Pulmonary hypertension: newer concepts in diagnosis and management. Clin Cardiol 1997; 20: 676–82
Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004; 351: 1655–65
Tuder RM, Cool CD, Yeager M, et al. The pathobiology of pulmonary hypertension: endothelium. Clin Chest Med 2001; 22: 405–18
Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004; 109: 159–65
Morris CR, Teehankee C, Kato G, et al. Decreased arginine bioavailability contributes to the pathogenesis of pulmonary artery hypertension. American College of Cardiology Annual Meeting; 2005 Mar 6–9; Orlando (FL)
Xu W, Kaneko TF, Zheng S, et al. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 2004; 18: 1746–8
Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle hemoglobinopathies. Am J Med 1982; 73: 814–21
Van Enk A, Visschers G, Jansen W, et al. Maternal death due to sickle cell chronic lung disease. Br J Obstet Gynaecol 1992; 99: 162–3
Simmons BE, Santhanam V, Castaner A, et al. Two-dimensional echo and Doppler ultrasonographic findings in the hearts of adult patients with sickle cell anemia. Arch Intern Med 1988; 148: 1526–8
Norris SL, Johnson C, Haywood LJ. Left ventricular filling pressure in sickle cell anemia. J Assoc Acad Minor Phys 1992; 3: 20–3
Adedeji MO, Cespedes J, Allen K, et al. Pulmonary thrombotic arteriopathy in patients with sickle cell disease. Arch Pathol Lab Med 2001; 125: 1436–41
Haque AK, Grinberg AR, Lencioni M, et al. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002; 33(33): 1037–43
Morris CR, Morris Jr SM, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003; 168: 63–9
Castro O. Systemic fat embolism and pulmonary hypertension in sickle cell disease. Hematol Oncol Clin North Am 1996; 10: 1289–303
Steward GW, Amess JA, Eber SW, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol 1996; 93: 303–10
Hoeper MM, Niedermeyer J, Hoffmeyer F, et al. Pulmonary hypertension after splenectomy? Ann Intern Med 1999; 130: 506–9
Aessopos A, Stamatelow G, Skoumas V, et al. Pulmonary hypertension and right heart failure in patients with B-thalassemia intermedia. Chest 1995; 107: 50–3
Powars DR, Pegelow CH. The spleen in sickle cell disease and thalassemia. Am J Pediatr Hematol Oncol 1979; 1(4): 343–53
Aldrich TK, Dhuper SK, Patwa NS, et al. Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia. J Appl Physiol 1996; 80: 531–9
Setty BN, Stuart MJ, Dampier C, et al. Hypoxaemia in sickle cell disease: biomarker modulation and relevance to pathophysiology. Lancet 2003; 362: 1450–5
Setty BN, Stuart MJ. Vascular cell adhesion molecule-1 is involved in mediating hypoxia- induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 1996; 88: 2311–20
Solovey A, Lin Y, Browne P, et al. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med 1997; 337(22): 1584–90
Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Blood 1997; 89(5): 1787–92
Phelan M, Perrine SP, Brauer M, et al. Sickle erythrocytes, after sickling, regulate the expression of the endothelin-1 gene and protein in human endothelial cells in culture. J Clin Invest 1995; 96: 1145–51
Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest 2000; 106: 411–20
Osarogiagbon UR, Choong S, Belcher JD, et al. Reperfusion injury pathophysiology in sickle cell transgenic mice. Blood 2000; 96: 314–20
Key NS, Slungaard A, Dandelet L, et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 1998 Jun 1; 91(11): 4216–23
Powars D, Weidmen JA, Odom-Maryon T, et al. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine (Baltimore) 1988; 67: 66–76
Liesner RJ, Vandenberghe FA. Sudden death in sickle cell disease. J R Soc Med 1993; 86: 484–5
Romero Mestre JC, Hernandez A, Agramonte O, et al. Cardiovascular autonomic dysfunction in sickle cell anemia: a possible risk factor for sudden death? Clin Auton Res 1997; 7: 121–5
Escoffery C, Shirley S. Causes of sudden natural death in Jamaica: a medicolegal (coroner’s) autopsy study from the University Hospital of the West Indies. Forensic Sci Int 2002; 129: 116–21
McGoon M, Gutterman D, Steen V, et al. Screening, early detection and diagnosis of pulmonary artery hypertension. Chest 2004; 126: 14S–34S
Minter K, Gladwin M. Pulmonary complications of sickle cell anemia: a need for increased recognition, treatment, and research. Am J Respir Crit Care Med 2001; 164: 2016–9
Hammond TG, Mosesson MW. Fatal small-bowel necrosis and pulmonary hypertension in sickle cell disease. Arch Intern Med 1989; 149: 447–8
Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002–12
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nat Med 1987; 327: 524–6
Ignarro LJ. Heme-dependent activation of soluble guanylate cyclase by nitric oxide: regulation of enzyme activity by porphyrins and metalloporphyrins. Semin Hematol 1989; 26: 63–76
Peng H-B, Spiecker M, Liao J. Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation. J Immunol 1998; 161: 1970–6
Kunes J, Hojna S, Kadlecova M, et al. Altered balance of vasoactive systems in experimental hypertension: the role of relative NO deficiency. Physiol Res 2004; 53Suppl. 1: S23–34
Pieper GM. Review of alterations in endothelial nitric oxide production in diabetes: protective role of arginine on endothelial dysfunction. Hypertension 1998; 31: 1047–60
de Boer J, Duyvendak M, Schuurman FE, et al. Role of L-arginine in the deficiency of nitric oxide and airway hyperreactivity after the allergen-induced early asthmatic reaction in guinea-pigs. Br J Pharmacol 1999; 128: 1114–20
de Boer J, Meurs H, Coers W, et al. Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study. Br J Pharmacol 1996; 119: 1109–16
de Gouw HW, Hendriks J, Woltman AM, et al. Exhaled nitric oxide (NO) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma. Am J Respir Crit Care Med 1998; 158: 315–9
Creager MA, Gallagher SJ, Girerd XJ, et al. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992; 90: 1248–53
Tsao PS, McEvoy LM, Drexler H, et al. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 1994; 89(5): 2176–82
Napoli C, Loscalzo J. Nitric oxide and other novel therapies for pulmonary hypertension. J Cardiovasc Pharmacol Ther 2004; 9: 1–8
Hampl V, Herget J. Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol Rev 2000; 80: 1337–72
Reiter CD, Gladwin MT. An emerging role for nitric oxide in sickle cell disease vascular homeostasis and therapy. Curr Opin Hematol 2003; 10: 99–107
Morris CR, Kuypers FA, Larkin S, et al. Patterns of arginine and nitric oxide in sickle cell disease patients with vaso-occlusive crisis and acute chest syndrome. J Pediatr Hematol Oncol 2000; 22: 515–20
Gladwin M, Schechter A, Ognibene F, et al. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 2003; 107: 271–8
Kaul DK, Liu X, Chang H, et al. Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. J Clin Invest 2004; 114: 1136–45
Reiter C, Wang X, Tanus-Santos J, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002; 8: 1383–9
Nath KA, Katusic ZS, Gladwin MT. The perfusion paradox and vascular instability in sickle cell disease. Microcirculation 2004; 11(2): 179–93
Asian M, Ryan T, Adler B, et al. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci U S A 2001; 98: 15215–20
Kaul DK, Liu XD, Fabry ME, et al. Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse. Am J Physiol Heart Circ Physiol 2000; 278: H1799–806
Nath KA, Shah V, Haggard JJ, et al. Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease. Am J Physiol Regul Integr Comp Physiol 2000; 279(6): R1949–55
Eberhardt RT, McMahon L, Duffy SJ, et al. Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels. Am J Hematol 2003; 74: 104–11
Belhassen L, Pelle G, Sediame S, et al. Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress-mediated vasodilation. Blood 2001; 97: 1584–9
Rees DC, Cervi P, Grimwade D, et al. The metabolites of nitric oxide in sickle-cell disease. Br J Haematol 1995; 91: 834–7
Lonsdorfer J, Bogui P, Otayeck A, et al. Cardiorespiratory adjustments in chronic sickle cell anemia. Bull Eur Physiopathol Respir 1983; 19: 339–44
Johnson CS, Giorgio AJ. Arterial blood pressure in adults with sickle cell disease. Arch Intern Med 1981; 141: 891–3
Karayaylali I, Onal M, Yildizer K, et al. Low blood pressure, decreased incidence of hypertension, and renal cardiac, and autonomic nervous system functions in patients with sickle cell syndromes. Nephron 202; 91: 535–7
Rodgers GP, Walker EC, Podgor MJ. Is ‘relative’ hypertension a risk factor for vaso-occlusive complications in sickle cell disease? Am J Med Sci 1993; 305(3): 150–6
Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997; 102(2): 171–7
Lopez BL, Barnett J, Ballas SK, et al. Nitric oxide metabolite levels in acute vaso-occlusive sickle-cell crisis. Acad Emerg Med 1996; 3: 1098–103
Lopez B, Davis-Moon L, Ballas S. Sequential nitric oxide measurements during the emergency department treatment of acute vasoocclusive sickle cell crisis. Am J Hematol 2000; 64: 15–9
Dias-Da-Motta P, Arruda V, Muscara M, et al. The release of nitric oxide and Superoxide anion by neutrophils and mononuclear cells from patients with sickle cell anaemia. Br J Haematol 1996; 93: 333–40
Demiryurek A, Dakici I, Danzik I. Peroxynitrite: a putative cytotoxin. Pharm Toxicol 1998; 82: 113–7
Xia Y, Dawson V, Dawson T, et al. Nitric oxide synthase generates Superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci U S A 1996; 93: 6770–4
Osei SY, Ahima RS, Fabry ME, et al. Immunohistochemical localization of hepatic nitric oxide synthase in normal and transgenic sickle cell mice: the effect of hypoxia. Blood 1996; 88: 3583–8
Bank N, Aynedjian H, Qiu J, et al. Renal nitric oxide synthases in transgenic sickle cell mice. Kidney Int 1996; 50: 184–9
Bassenge E. Endothelial function in different organs. Prog Cardiovasc Dis 1996; 39: 209–28
Graido-Gonzalez E, Doherty LC, Bergreen EW, et al. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vasoocclusive sickle. Blood 1998; 92: 2551–5
Rubin L, Badesch D, Barst R, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903
Dupuis J. Endothelin-receptor antagonists in pulmonary hypertension. Lancet 2001; 358: 1113–4
Schnog JB, Rojer RA, MacGillavry MR, et al. Steady-state sVCAM-1 serum levels in adults with sickle cell disease. Ann Hematol 2003; 82: 109–13
Duits AJ, Pieters RC, Saleh AW, et al. Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific increment during vasoocclusive crisis. Clin Immunol Immunopathol 1996; 81: 96–8
Natarajan M, Udden MM, McIntire LV. Adhesion of sickle red blood cells and damage to interleukin-1 beta stimulated endothelial cells under flow in vitro. Blood 1996; 87(11): 4845–52
Swerlick RA, Eckman JR, Kumar A, et al. Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium. Blood 1993; 82(6): 1891–9
Gee BE, Platt OS. Sickle reticulocytes adhere to VCAM-1. Blood 1995; 85(1): 268–74
Stuart M, Setty Y. Sickle cell acute chest syndrome: pathogenesis and rational for treatment. Blood 1999; 94: 1555–60
Kato GJ, Martyr S, Blackwelder WC, et al. Endothelial dysfunction in patients with sickle cell disease is associated with haemolytic rate, multi-organ failure, and risk of death. Blood; Epub 2005 Nov 15
Hallemeesch MM, Lamers WH, Deutz NE. Reduced arginine availability and nitric oxide production. Clin Nutr 2002; 21(4): 273–9
Enwonwu CO. Increased metabolic demand for arginine in sickle cell anaemia. Med Sci Res 1989; 17: 997–8
Enwonwu CO, Xu X, Turner E. Nitrogen metabolism in sickle cell anemia: free amino acids in plasma and urine. Am J Med Sci 1990; 300: 366–71
Waugh W, Daeschner C, Files B, et al. Evidence that L-arginine is a key amino acid in sickle cell anemia: a preliminary report. Nutr Res 1999; 19: 501–18
Mendes Ribeiro AC, Brunini TM. L-arginine transport in disease. Curr Med Chem Cardiovasc Hematol Agents 2004; 2: 123–31
Morris CR, Kuypers FA, Larkin S, et al. Arginine therapy: a novel strategy to increase nitric oxide production in sickle cell disease. Br J Haematol 2000; 111: 498–500
Lopez B, Kreshak A, Morris CR, et al. L-arginine levels are diminished in adult acute vaso-occlusive sickle cell crisis in the emergency department. Br J Haematol 2003; 120: 532–4
Girgis RE, Qureshi MA, Abrams J, et al. Decreased exhaled nitric oxide in sickle cell disease: relationship to chronic lung involvement. Am J Hematol 2003; 72: 177–84
Sullivan K, Kissoon N, Duckworth L, et al. Low exhaled nitric oxide and a polymorphism in the NOS I gene is associated with acute chest syndrome. Am J Respir Crit Care Med 2001; 164: 2186–90
Heinzel B, John M, Klatt P, et al. Ca2+/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J 1992; 281: 627–30
Lee J, Ryu H, Ferrante R, et al. Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci U S A 2003; 100: 4843–8
El-Gayar S, Thuring-Nahler H, Pfeilschifter J, et al. Translational control of inducible nitric oxide synthase by IL-13 and arginine availability in inflammatory macrophages. J Immunol 2003; 171: 4561–8
Kamada Y, Nagaretani H, Tamura S, et al. Vascular endothelial dysfunction resulting from L-arginine deficiency in a patient with lysinuric protein intolerance. J Clin Invest 2001; 108: 717–24
Morris Jr SM. Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr 2002; 22: 87–105
Morris Jr SM, Bhamidipati D, Kepka-Lenhart D. Human type II arginase: sequence analysis and tissue-specific expression. Gene 1997; 193: 157–61
Vockley JG, Jenkinson CP, Shukula H, et al. Cloning and characterization of the human type II arginase gene. Genomics 1996; 38: 118–23
Gotoh T, Sonoki T, Nagasaki A, et al. Molecular cloning of cDNA for nonhepatic mitochondrial arginase (arginase II) and comparison of its induction with nitric oxide synthase in a murine macrophage-like cell line. FEBS Lett 1996; 395: 119–22
Kim P, Iyer R, Lu K, et al. Expression of the liver form of arginase in erythrocytes. Mol Genet Metab 2002; 76: 100–10
Azizi E, Dror Y, Wallis K. Arginase activity in erythrocytes of healthy and ill children. Clin Chim Acta 1970; 28: 391–6
Morris Jr SM. Regulation of arginine availability and its impact on NO synthesis. In: Ignarro L, editor. Nitric oxide: biology and pathobiology. San Diego (CA): Academic Press, 2000: 187–97
Mori M, Gotoh T. Relationship between arginase activity and nitric oxide production. In: Ignarro L, editor. Nitric oxide: biology and pathology. San Diego (CA): Academic Press, 2000: 199–208
Belfiore F. Enzymatic activities of the blood serum in thalassemia and in thalassodrepanocytosis. Riforma Med 1964; 78: 1052–5
Reynolds J, Follette JH, Valentine WH. The arginase activity of erythrocytes and leukocytes with particular reference to pernicious anemia and thalassemia major. J Lab Clin Med 1957; 50: 78–92
Verresen D, De Backer W, Van Meerbeeck J, et al. Spherocytosis and pulmonary hypertension: coincidental occurrence or causal relationship? Eur Respir J 1991; 4: 629–31
Heller PG, Grinberg AR, Lencioni M, et al. Pulmonary hypertension in paroxysmal nocturnal hemoglobinuria. Chest 1992; 102: 642–3
Labrune P, Sittoun J, Duvaltier I, et al. Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr 1999; 158: 734–9
Stuard ID, Heusinkveld RS, Moss AJ. Microangiopathic haemolytic anemia and thrombocytopenia in primary pulmonary hypertension. N Engl J Med 1972; 287: 869–70
Jubelirer SJ. Primary pulmonary hypertension: its association with microangiopathic haemolytic anemia and thrombocytopenia. Arch Intern Med 1991; 151: 1221–3
Chou R, DeLoughery TG. Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency. Am J Hematol 2001; 67: 197–9
Mehta S, Stewart D, Langleben D, et al. Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation 1995; 92: 1539–45
Archer S, Djaballah K, Humbert M, et al. Nitric oxide deficiency in fenfluramine and dexfenfluramine-induced pulmonary hypertension. Am J Respir Crit Care Med 1998; 158: 1061–7
Cooper C, Landzberg M, Anderson T, et al. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation 1996; 93: 266–71
Kaneko F, Arroliga A, Dweik R, et al. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 1998; 158: 917–23
Jison ML, Munson PJ, Barb JJ, et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. Blood 2004; 104: 270–80
Morris CR, Poljakovic M, Lavrisha L, et al. Decreased arginine bioavailability and increased serum arginase activity in asthma. Am J Respir Crit Care Med 2004; 170: 148–53
Meurs H, Schuurman FE, Duyvendak M, et al. Deficiency of nitric oxide in polycation-induced airway hyperreactivity. Br J Pharmacol 1999; 126: 559–62
Ricciardolo FL, Geppetti P, Mistretta A, et al. Randomized double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma. Lancet 1996; 348: 374–7
Ricciardolo FL, Di Maria GU, Mistretta A, et al. Impairment of bronchoprotection by nitric oxide in severe asthma. Lancet 1997; 350: 1297–8
Ricciardolo FL, Timmers MC, Gepetti P, et al. Allergen-induced impairment of bronchoprotective nitric oxide synthesis in asthma. J Allergy Clin Immunol 2001; 108: 198–204
Zimmerman N, King NE, Laporte J, et al. Dissection of expeirmental asthma with DNA microarray analysis identifies arginase in asthma pathogensisi. J Clin Invest 2003; 111: 1863–74
Meurs H, McKay S, Maarsingh H, et al. Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyper-responsiveness. Br J Pharmacol 2002; 136: 391–8
Meurs H, Hamer MA, Pethe S, et al. Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity. Br J Pharmacol 2000; 130: 1793–8
Meurs H, Maarsingh H, Zaagsma J. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol Sci 2003; 24: 450–5
Raghupathy R, Haider MZ, Azizieh F, et al. Th1 and Th2 cytokine profiles in sickle cell disease. Acta Haematol 2000; 103: 197–202
Komai M, Tanaka H, Masuda T, et al. Role of Th2 responses in the development of allergen-induced airway remodeling in a murine model of allergic asthma. Br J Pharmacol 2003; 138: 912–20
Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54: 825–57
Ahmed S, Siddiqui AK, Sadiq A, et al. Echocardiographic abnormalities in sickle cell disease. Am J Hematol 2004; 76(3): 195–8
Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology 1997; 87: 988–90
Sullivan KJ, Goodwin SR, Evangelist J, et al. Nitric oxide successfully used to treat acute chest syndrome of sickle cell disease in a young adolescent. Crit Care Med 1999; 27: 2563–8
Vichinsky E, Neumayr L, Earles A, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000; 342: 1855–65
Koumbourlis A, Zar H, Hurlet-Jensen A, et al. Prevalence and reversibility of lower airway obstruction in children with sickle cell disease. J Pediatr 2001; 138: 188–92
Leong M, Dampier C, Varlotta L, et al. Airway hyperreactivity in children with sickle cell disease. J Pediatr 1997; 131: 278–83
Rastogi D, Ngai P, Barst RJ, et al. Lower airway obstruction, bronchial hyperresponsiveness, and primary pulmonary hypertension in children. Pediatr Pulmonol 2004; 37: 50–5
Arnal J-F, Munzel T, Venema R, et al. Interactions between L-arginine and L-glutamine change endothelial NO production; an effect independent of NO synthase substrate availability. J Clin Invest 1995; 95: 2565–72
Kurz S, Harrison D. Insulin and the arginine paradox. J Clin Invest 1997; 99: 369–70
Wu G, Morris Jr SM. Arginine metabolism: nitric oxide and beyond. Biochem J 1998; 336: 1–17
Graf P, Forstermann U, Closs E. The transport activity of the human cationic amino acid transporter hCAT-1 is downregulated by activation of protein kinase C. Br J Pharmacol 2001; 132: 1193–200
Zharikov S, Block E. Association of L-arginine transporters with fodrin: implications for hypoxic inhibition of arginine uptake. Am J Physiol Lung Cell Mol Physiol 2000; 278: L111–7
Closs EI, Mann GE. Membrane transport of L-arginine and cationic amino acid analogs. San Diego (CA): Academic Press, 2000
Closs EI. Expression, regulation and function of carrier proteins for cationic amino acids. Curr Opin Nephrol Hypertens 2002; 11: 99–107
Wu G, Morris Jr SM. Metabolic and therapeutic aspects of amino acids in clinical nutrition. CRC Press: Boca Raton (FL), 2004
Schnog JB, Jager EH, van der Dijs FP, et al. Evidence for a metabolic shift of arginine metabolism in sickle cell disease. Ann Hematol 2004; 83: 371–5
Natta CL, Motyczka AA, Kremzner LT. Polyamines in sickle cell disease. Biochem Med 1980; 23(2): 144–9
Natta CL, Motyczka AA, Kremzner LT. Polyamines and globin binding in sickle cell disease. Am J Pediatr Hematol Oncol 1982; 4(1): 73–6
VanderJagt DJ, Kanellis GJ, Isichei C, et al. Serum and urinary amino acid levels in sickle cell disease. J Trop Pediatr 1997; 43: 220–5
Zimmermann N, King NE, Laporte J, et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 2003; 111: 1863–74
Wei LH, Wu Jr SM, Ignarro LJ. Elevated arginase I expression in rat aortic smooth muscle cells increases cell proliferation. Proc Natl Acad Sci U S A 2001; 98: 9260–4
Li H, Meininger CJ, Kelly KA, et al. Activities of arginase I and II are limiting for endothelial cell proliferation. Am J Physiol Regul Integr Comp Physiol 2002; 282: R64–9
Vallance P. The asymmetrical dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in the regulation of nitric oxide generation. Clin Sci 2001; 100: 159–60
Cooke JP, Mont-Reynaud R, Tsao PS, et al. Nitric oxide and vascular disease. In: Ignarro LJ, editor. Nitric oxide: biology and pathology. New York: Academic Press, 2000: 759–83
Stuhlinger MC, Oka RK, Graf EE, et al. Endothelial dysfunction induced by hyperhomocyst (e)inemia: role of asymmetric dimethylarginine. Circulation 2003; 108: 933–8
Boger RH, Bode-Boger SM. Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular disease. Semin Thromb Hemost 2000; 26: 539–45
Millatt LJ, Whitley GS, Li D, et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 2003; 108(12): 1493–8
Gorenflo M, Zheng C, Werle E, et al. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 2001; 37(4): 489–92
Wu G, Meininger CJ, Knabe DA, et al. Arginine nutrition in development, health and disease. Curr Opin Clin Nutr Metab Care 2000; 3(1): 59–66
Wu G. Intestinal mucosal amino acid catabolism. J Nutr 1998; 128: 1249–52
Waugh WH, Daeschner CW, Files BA, et al. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc 2001; 93: 363–71
Merimee TJ, Rabinowitz D, Riggs L, et al. Plasma growth hormone after arginine infusion. N Engl J Med 1967; 276: 434–9
Merimee TJ, Rabinowitz D, Fineberg S. Arginine-initiated release of human growth hormone. N Engl J Med 1969; 28: 1434–8
Barbul A, Rettura G, Levenson SM, et al. Wound healing and thymotropic effects of arginine: a pituitary mechanism of action. Am J Clin Nutr 1983; 37: 786–94
Solomons C, Cotton EK, Dubois R. The use of buffered L-arginine in the treatment of cystic fibrosis. Pediatrics 1971; 47: 384–90
Lerman A, Burnett JC, Higano ST, et al. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in human. Circulation 1998; 97: 2123–8
Perrine SP, Olivieri NF, Faller DV, et al. Butyrate derivatives: new agents for stimulating fetal globin production in the beta-globin disorders. Am J Pediatr Hematol Oncol 1994; 16: 67–71
Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993; 328(2): 81–6
Evans RW, Fernstrom JD, Thompson J, et al. Biochemical responses of healthy subjects during dietary supplementation with L-arginine. J Nutr Biochem 2004; 15: 534–9
Boger RH, Bode-Boger SM. The clinical pharmacology of L-arginine. Annu Rev Pharmacol Toxicol 2001; 41: 79–99
Martin WJ, Matzke GR. Treating severe metabolic alkalosis. Clin Pharm 1982; 1(1): 42–8
Barbul A. Arginine: biochemistry, physiology and therapeutic implications. JPEN J Parenter Enterai Nutr 1986; 10: 227–38
Adams MR, Forsyth CJ, Jessup W, et al. Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men. J Am Coll Cardiol 1995; 26: 1054–61
Tangphao O, Chalon S, Moreno H, et al. Pharmacokinetics of L-arginine during chronic administration to patients with hypercholesterolaemia. Clin Sci 1999; 96: 199–207
Morris Jr SM. Enzymes of arginine metabolism. J Nutr 2004; 134: 2743S–7S
Morris Jr SM. Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care 2004; 7: 45–51
Maxwell AJ, Cooke JP. Cardiovascular effects of L-arginine. Curr Opin Nephrol Hypertens 1998; 7: 63–70
Morris CR, Vichinsky EP, van Warmerdam J, et al. Hydroxyurea and arginine therapy: impact on nitric oxide production in sickle cell disease. J Pediatr Hematol Oncol 2003; 25: 629–34
American Society of Health Systems Pharmacists. In: McEvoy G, editor. Bethesda (MD): American Hospital Formulary Service: Drug Information, 1999: 2185–6
Siani A, Pagano E, Iacone R, et al. Blood pressure and metabolic changes during dietary L-arginine supplementation in humans. Am J Hypertens 2000; 13 (5 Pt 1): 547–51
Reyes AA, Karl IE, Klahr S. Role of arginine in health and in renal disease. Am J Physiol 1994; 267 (3 Pt 2): F331–46
Tews JK, Bradford AM, Harper AE. Induction of lysine imbalance in rats: relationships between tissue amino acids and diet. J Nutr 1981; 111: 968–78
Krauss JS, Freant LJ, Lee JR. Gastrointestinal pathology in sickle cell disease. Ann Clin Lab Sci 1998; 28(1): 19–23
Bauer TW, Moore GW, Hutchins GM. The liver in sickle cell disease: a clinicopathologic study of 70 patients. Am J Med 1980; 69(6): 833–7
Hertz P, Richardson J. Arginine-induced hyperkalemia in renal failure patients. Arch Intern Med 1972; 130: 778–80
Gerard JM, Luisiri A. A fatal overdose of arginine hydrochloride. J Toxicol Clin Toxicol 1997; 35(6): 621–5
Kharitonov SA, Lubec G, Lubec B, et al. L-arginine increases exhaled nitric oxide in normal human subjects. Clin Sci (Colch) 1995; 88(2): 135–9
Solomons C, Hathaway W, Cotton E. L-arginine, the sickling phenomenon, and cystic fibrosis. Pediatrics 1972; 49: 933
Grasemann H, Grasemann C, Kurtz F, et al. Oral L-arginine supplementation in cystic fibrosis patients: a placebo-controlled study. Eur Respir J 2005; 25(1): 62–8
Everard ML, Donnelly D. A pilot study of oral L-arginine in cystic fibrosis. J Cyst Fibros 2005; 4(1): 67–9
Cooke JP, Singer AH, Tsao P, et al. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992; 90: 1168–72
Nijkamp FP, Folkerts G. Nitric oxide and bronchial hyperresponsiveness. Arch Int Pharmacodyn Ther 1995; 329: 81–96
Hamid Q, Springall DR, Riveros-Morena V, et al. Induction of nitric oxide synthase in asthma. Lancet 1993; 342: 1510–3
Gornik HL, Creager MA. Arginine and endothelial and vascular health. J Nutr 2004; 134 (10 Suppl.): 2880S–7S
Appleton J. Arginine: clinical potential of a semi-essential amino. Altern Med Rev 2002; 7(6): 512–22
Kawano T, Nomura M, Nisikado A, et al. Supplementation of L-arginine improves hypertension and lipid metabolism but not insulin resistance in diabetic rats. Life Sci 2003; 73(23): 3017–26
Drexler H, Zeiher AM, Meinzer K, et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991; 338: 1546–50
Kernohan AF, McIntyre M, Hughes DM, et al. An oral yohimbine/L-arginine combination (NMI 861) for the treatment of male erectile dysfunction: a pharmacokinetic, pharmacodynamic and interaction study with intravenous nitroglycerine in healthy male subjects. Br J Clin Pharmacol 2005; 59(1): 85–93
Klotz T, Mathers MJ, Braun M, et al. Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study. Urol Int 1999; 63(4): 220–3
Rytlewski K, Olszanecki R, Korbut R, et al. Effects of prolonged oral supplementation with l-arginine on blood pressure and nitric oxide synthesis in preeclampsia. Eur J Clin Invest 2005; 35(1): 32–7
Preli RB, Klein KP, Herrington DM. Vascular effects of dietary L-arginine supplementation. Atherosclerosis 2002; 162(1): 1–15
Rector TS, Bank AJ, Mullen KA, et al. Randomized, double-blind, placebo controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996; 93: 2135–41
Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med 2001; 163: 887–91
McCaffrey M, Bose C, Reiter P, et al. Effect of L-arginine infusion on infants with persistent pulmonary hypertension of the newborn. Biol Neonate 1995; 67: 240–3
Baudouin SV, Bath P, Martin JF, et al. L-arginine infusion has no effect on systemic haemodynamics in normal volunteers, or systemic and pulmonary haemodynamics in patients with elevated pulmonary vascular resistance. Br J Clin Pharmacol 1993; 36: 45–9
Mitani Y, Maruyama K, Sakurai M. Prolonged administration of L-arginine ameliorates chronic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 1997; 96(2): 689–97
Surdacki A, Zmudka K, Bieron K, et al. Lack of beneficial effects of L-arginine infusion in primary pulmonary hypertension. Wien Klin Wochenschr 1994; 106: 521–6
Sher GD, Olivieri NG. Rapid healing of leg ulcers during arginine butyrate therapy in patients with sickle cell disease and thalassemia. Blood 1994; 84: 2378–80
Sher GD, Ginder GD, Little J, et al. Extended therapy with intravenous arginine butyrate in patients with b-hemoglobinopathies. N Engl J Med 1995; 332: 1606–10
Sutton M, Weinberg R, Padilla M, et al. Development of pulmonary hypertension in sickle cell disease in spite of a response to hydroxyurea. In: Ohene-Frempong K, editor. 24th Annual Meeting of the National Sickle Cell Disease Program; 2000 Apr; Philadelphia (PA), 2000: 87a.
Gladwin M, Shelhamer J, Ognibene F, et al. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol 2002; 116: 436–44
Nahavandi M, Wyche MO, Perlin E, et al. Nitric oxide metabolites in sickle cell anemia patients after oral administration of hydroxyurea. Hematology 2000; 5: 235–9
Glover R, Ivy E, Orringer E, et al. Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea. Mol Pharmacol 1999; 55: 1006–10
Kim-Shapiro DB, King SB, Bonifant CL, et al. Time resolved absorption study of the reaction of hydroxyurea with sickle cell hemoglobin. Biochim Biophys Acta 1998; 1380(1): 64–74
Romero J, Suzuka S, Nagel R, et al. Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity. Blood 2002; 99: 1103–8
Gladwin M, Schechter A. Nitric oxide therapy in sickle cell disease. Semin Hematol 2001; 38: 333–42
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. JAMA 2003; 289: 1136–42
Oppert M, Jorres A, Barckow D, et al. Inhaled nitric oxide for ARDS due to sickle cell disease. Swiss Med Wkly 2004; 134: 165–7
de Franceschi L, Baron A, Scarpa A, et al. Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/ reoxygenation. Blood 2003; 102: 1087–96
Roberts J, Fineman J, Morin F, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336: 605–10
Pepke-Zaba J, Higenbottam T, Dinh-Xuan A, et al. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991; 338: 1173–4
Sasaki S, Asano M, Ukai T, et al. Nitric oxide formation and plasma L-arginine levels in pulmonary hypertensive rats. Respir Med 2004; 98: 205–12
Vosatka R, Kashyap S, Trifiletti R. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 1994; 66: 65–70
Pearson D, Dawling S, Walsh W, et al. Neonatal pulmonary hypertension: ureacycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 2001; 344: 1832–8
Schnader J. Top ten list in pulmonary vascular disease. Chest 2005; 127(2): 652–4
Stuehr DJ, Kwon N, Nathan CF, et al. N-Hydroxyl-L-arginine is an intermediate in the biosynthesis of nitric oxide for L-arginine. J Biol Chem 1991; 266: 6259–63
Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors, and arginase competition for L-arginine utilization. Cell Mol Life Sci 1999; 55: 1015–28
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351(14): 1425–36
Acknowledgments
Supported in part by National Institutes of Health grants HL-04386-05 and MO1-RR01271, Pediatric Clinical Research Center.
The author wishes to acknowledge the contributions of Drs Sidney Morris, Jr and Mark Gladwin for helpful discussions and Dr Sidney Morris, Jr for critical review of the manuscript.
The author has no conflicts of interest directly relevant to the content of this review.
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Morris, C.R. New Strategies for the Treatment of Pulmonary Hypertension in Sickle Cell Disease. Treat Respir Med 5, 31–45 (2006). https://doi.org/10.2165/00151829-200605010-00003
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DOI: https://doi.org/10.2165/00151829-200605010-00003