Nitric oxide deficiency in pulmonary hypertension: Pathobiology and implications for therapy

Pulmonary Circulation

Volumn 3, Issue 1, 2013, Pages 20-30

  Tonelli, Adriano R ^a   Haserodt, Sarah ^a   Aytekin, Metin ^a,b   Dweik, Raed A ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

^b ERCIYES UNIVERSITY   (Turkey)

Author keywords

Nitric oxide; Physiopathology and therapeutics; Pulmonary hypertension

Indexed keywords

EID: 84885926946     PISSN: 20458932     EISSN: 20458940     Source Type: Journal    
DOI: 10.4103/2045-8932.109911     Document Type: Review

References (171)

1. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216-23.
2. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009;54:S3-9.
3. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: Pulmonary arterial hypertension. Nat Rev Cardiol 2011;8:443-55.
4. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987;84:9265-9.
5. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6.
6. Nathan C, Xie QW. Nitric oxide synthases: Roles, tolls, and controls. Cell 1994;78:915-8.
7. Schmidt HH, Walter U. NO at work. Cell 1994;78:919-25.
8. Gaston B, Drazen JM, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 1994;149:538-51.
9. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992;6:3051-64.
10. Dweik RA, Erzurum SC. Effects of Nitric Oxide and Cyclic GMP on Smooth Muscle Proliferation. In: Moss J, editors. LAM and Other Diseases Characterized by Smooth Muscle Proliferation. New York: Marcel Dekker Inc; 1999. p. 333-49.
11. Stuehr DJ, Griffith OW. Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol 1992;65:287-346.
12. Dweik RA, Laskowski D, Ozkan M, Farver C, Erzurum SC. High levels of exhaled nitric oxide (NO) and NO synthase III expression in lesional smooth muscle in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2001;24:414-8.
13. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-12.
14. Coggins MP, Bloch KD. Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol 2007;27:1877-85.
15. Stuehr DJ. Mammalian nitric oxide synthases. Biochim Biophys Acta 1999;1411:217-30.
16. Dweik RA. Nitric oxide, hypoxia, and superoxide: The good, the bad, and the ugly! Thorax 2005;60:265-7.
17. Dudzinski DM, Igarashi J, Greif D, Michel T. The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol 2006;46:235-76.
18. Newby AC, Southgate KM, Assender JW. Inhibition of vascular smooth muscle cell proliferation by endothelium-dependent vasodilators. Herz 1992;17:291-9.
19. Nathan C, Xie QW. Regulation of biosynthesis of nitric oxide. J Biol Chem 1994;269:13725-8.
20. Barnes PJ, Dweik RA, Gelb AF, Gibson PG, George SC, Grasemann H, et al. Exhaled nitric oxide in pulmonary diseases: A comprehensive review. Chest 2010;138:682-92.
21. Guo FH, De Raeve HR, Rice TW, Stuehr DJ, Thunnissen FB, Erzurum SC. Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc Natl Acad Sci U S A 1995;92:7809-13.
22. Ward JK, Belvisi MG, Fox AJ, Miura M, Tadjkarimi S, Yacoub MH, et al. Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. J Clin Invest 1993;92:736-42.
23. Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-42.
24. Shaul PW. Regulation of endothelial nitric oxide synthase: Location, location, location. Annu Rev Physiol 2002;64:749-74.
25. Bernareggi M, Mitchell JA, Barnes PJ, Belvisi MG. Dual action of nitric oxide on airway plasma leakage. Am J Respir Crit Care Med 1997;155:869-74.
26. Ricciardolo FL, Sterk PJ, Gaston B, Folkerts G. Nitric oxide in health and disease of the respiratory system. Physiol Rev 2004;84:731-65.
27. Fagan KA, Tyler RC, Sato K, Fouty BW, Morris KG Jr, Huang PL, et al. Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation. Am J Physiol 1999;277:L472-8.
28. Dweik RA, Laskowski D, Abu-Soud HM, Kaneko F, Hutte R, Stuehr DJ, et al. Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism. J Clin Invest 1998;101:660-6.
29. Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC, Bevan JA, et al. Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res 1997;81:34-41.
30. Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: Cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci U S A 1990;87:8612-6.
31. Flam BR, Hartmann PJ, Harrell-Booth M, Solomonson LP, Eichler DC. Caveolar localization of arginine regeneration enzymes, argininosuccinate synthase, and lyase, with endothelial nitric oxide synthase. Nitric Oxide 2001;5:187-97.
32. Solomonson LP, Flam BR, Pendleton LC, Goodwin BL, Eichler DC. The caveolar nitric oxide synthase/arginine regeneration system for NO production in endothelial cells. J Exp Biol 2003;206:2083-7.
33. Hattori Y, Campbell EB, Gross SS. Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. Role in the regeneration or arginine for nitric oxide synthesis. J Biol Chem 1994;269:9405-8.
34. Schmidt HH, Lohmann SM, Walter U. The nitric oxide and cGMP signal transduction system: Regulation and mechanism of action. Biochim Biophys Acta 1993;1178:153-75.
35. Dweik RA. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 2002;360:886-7.
36. Garbers DL. Guanylyl cyclase receptors and their endocrine, paracrine, and autocrine ligands. Cell 1992;71:1-4.
37. McDonald LJ, Murad F. Nitric oxide and cyclic GMP signaling. Proc Soc Exp Biol Med 1996;211:1-6.
38. Murad F. Regulation of cytosolic guanylyl cyclase by nitric oxide: The NO-cyclic GMP signal transduction system. Adv Pharmacol 1994;26:19-33.
39. Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A 1994;91:7583-7.
40. Lincoln TM, Cornwell TL. Intracellular cyclic GMP receptor proteins. FASEB J 1993;7:328-38.
41. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003;93:280-91.
42. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: Structure, function and inhibition. Biochem J 2001;357:593-615.
43. Bulau P, Zakrzewicz D, Kitowska K, Leiper J, Gunther A, Grimminger F, et al. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol Lung Cell Mol Physiol 2007;292:L18-24.
44. Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler 2003;4:33-40.
45. Dweik RA. The lung in the balance: Arginine, methylated arginines, and nitric oxide. Am J Physiol Lung Cell Mol Physiol 2007;292:L15-7.
46. Ogawa T, Kimoto M, Sasaoka K. Purification and properties of a new enzyme, NG, NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 1989;264:10205-9.
47. Sy BMC, Dweik EE, Dweik RA. Arginine and nitric oxide. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. Modern nutrition in health and disease. 10th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005. p. 571-81.
48. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774-7.
49. Thomae KR, Nakayama DK, Billiar TR, Simmons RL, Pitt BR, Davies P. The effect of nitric oxide on fetal pulmonary artery smooth muscle growth. J Surg Res 1995;59:337-43.
50. Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res 1996;78:225-30.
51. Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. Am J Physiol 1990;259:H1921-7.
52. Geng Y, Hansson GK, Holme E. Interferon-gamma and tumor necrosis factor synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. Circ Res 1992;71:1268-76.
53. Stein CS, Fabry Z, Murphy S, Hart MN. Involvement of nitric oxide in IFN-gamma-mediated reduction of microvessel smooth muscle cell proliferation. Mol Immunol 1995;32:965-73.
54. Fukuo K, Hata S, Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, et al. Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 1996;27:823-6.
55. Schini VB, Vanhoutte PM. Role of the L-arginine-nitric oxide pathway in vascular smooth muscle. Eur Heart J 1993;14:16-21.
56. Thomae KR, Joshi PC, Davies P, Pitt BR, Billiar TR, Simmons RL, et al. Nitric oxide produced by cytokine-activated pulmonary artery smooth muscle cells is cytotoxic to cocultured endothelium. Surgery 1996;119:61-6.
57. Nunokawa Y, Tanaka S. Interferon-gamma inhibits proliferation of rat vascular smooth muscle cells by nitric oxide generation. Biochem Biophys Res Commun 1992;188:409-15.
58. Nakaki T, Nakayama M, Kato R. Inhibition by nitric oxide and nitric oxide-producing vasodilators of DNA synthesis in vascular smooth muscle cells. Eur J Pharmacol 1990;189:347-53.
59. Kolpakov V, Gordon D, Kulik TJ. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res 1995;76:305-9.
60. Cornwell TL, Arnold E, Boerth NJ, Lincoln TM. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am J Physiol 1994;267:C1405-13.
61. Clementi E, Sciorati C, Nistico G. Growth factor-induced Ca2+ responses are differentially modulated by nitric oxide via activation of a cyclic GMP-dependent pathway. Mol Pharmacol 1995;48:1068-77.
62. Nguyen T, Brunson D, Crespi CL, Penman BW, Wishnok JS, Tannenbaum SR. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci U S A 1992;89:3030-4.
63. Yang W, Ando J, Korenaga R, Toyo-oka T, Kamiya A. Exogenous nitric oxide inhibits proliferation of cultured vascular endothelial cells. Biochem Biophys Res Commun 1994;203:1160-7.
64. Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 1994;94:2036-44.
65. Fukuo K, Inoue T, Morimoto S, Nakahashi T, Yasuda O, Kitano S, et al. Nitric oxide mediates cytotoxicity and basic fibroblast growth factor release in cultured vascular smooth muscle cells. A possible mechanism of neovascularization in atherosclerotic plaques. J Clin Invest 1995;95:669-76.
66. Kim-Shapiro DB, Schechter AN, Gladwin MT. Unraveling the reactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol 2006;26:697-705.
67. Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS. Protein S-nitrosylation: Purview and parameters. Nat Rev Mol Cell Biol 2005;6:150-66.
68. Zweier JL, Wang P, Samouilov A, Kuppusamy P. Enzyme-independent formation of nitric oxide in biological tissues. Nat Med 1995;1:804-9.
69. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008;7:156-67.
70. Duranski MR, Greer JJ, Dejam A, Jaganmohan S, Hogg N, Langston W, et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J Clin Invest 2005;115:1232-40.
71. Gladwin MT, Kim-Shapiro DB. The functional nitrite reductase activity of the heme-globins. Blood 2008;112:2636-47.
72. Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells: The role of nitric oxide and S-nitrosohemoglobin. Annu Rev Physiol 2005;67:99-145.
73. Tsujino I, Miyamoto K, Nishimura M, Shinano H, Makita H, Saito S, et al. Production of nitric oxide (NO) in intrathoracic airways of normal humans. Am J Respir Crit Care Med 1996;154:1370-4.
74. Dweik RA, Erzurum SC. Regulation of nitric oxide (NO) synthases and gas phase NO by oxygen. In: Marczin N, Kharitonov SA, Yacoub MH, Barnes PJ, editors. Disease markers in exhaled breath. New York: Marcel Dekker Inc; 2003. p. 235-46.
75. Dweik RA, Guo FH, Uetani K, Erzurum SC. Nitric oxide synthase in the human airway epithelium. Zhongguo Yao Li Xue Bao 1997;18:550-2.
76. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, et al. Nitric oxide synthase in human and rat lung: Immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993;9:371-7.
77. Barnes PJ, Belvisi MG. Nitric oxide and lung disease. Thorax 1993;48:1034-43.
78. Dweik RA. The promise and reality of nitric oxide in the diagnosis and treatment of lung disease. Cleve Clin J Med 2001;68:486, 8, 90, 93.
79. Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, et al. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A 2001;98:2622-7.
80. Khatri SB, Hammel J, Kavuru MS, Erzurum SC, Dweik RA. Temporal association of nitric oxide levels and airflow in asthma after whole lung allergen challenge. J Appl Physiol 2003;95:436-40.
81. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006;355:354-64.
82. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006;355:343-53.
83. Stark AR. Inhaled NO for preterm infants-getting to yes? N Engl J Med 2006;355:404-6.
84. McCurnin DC, Pierce RA, Chang LY, Gibson LL, Osborne-Lawrence S, Yoder BA, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 2005;288:L450-9.
85. Zacharasiewicz A, Wilson N, Lex C, Erin EM, Li AM, Hansel T, et al. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 2005;171:1077-82.
86. Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: An observational study in adults with asthma. Clin Exp Allergy 2005;35:1175-9.
87. Smith AD, Cowan JO, Brassett KP, Filsell S, McLachlan C, Monti-Sheehan G, et al. Exhaled nitric oxide: A predictor of steroid response. Am J Respir Crit Care Med 2005;172:453-9.
88. Ischiropoulos H, Mendiguren I, Fisher D, Fisher AB, Thom SR. Role of neutrophils and nitric oxide in lung alveolar injury from smoke inhalation. Am J Respir Crit Care Med 1994;150:337-41.
89. Weber M, Lauer N, Mulsch A, Kojda G. The effect of peroxynitrite on the catalytic activity of soluble guanylyl cyclase. Free Radic Biol Med 2001;31:1360-7.
90. Firth AL, Yuan JX. Bringing down the ROS: A new therapeutic approach for PPHN. Am J Physiol Lung Cell Mol Physiol 2008;295:L976-8.
91. Farrow KN, Lakshminrusimha S, Reda WJ, Wedgwood S, Czech L, Gugino SF, et al. Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2008;295:L979-87.
92. Robbins CG, Horowitz S, Merritt TA, Kheiter A, Tierney J, Narula P, et al. Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia. Am J Physiol 1997;272:L903-7.
93. Lundberg JO, Farkas-Szallasi T, Weitzberg E, Rinder J, Lidholm J, Anggåard A, et al. High nitric oxide production in human paranasal sinuses. Nat Med 1995;1:370-3.
94. Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano 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.
95. Ozkan M, Dweik RA, Laskowski D, Arroliga AC, Erzurum SC. High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung 2001;179:233-43.
96. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-21.
97. Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:1642-4.
98. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925-32.
99. Mason NA, Springall DR, Burke M, Pollock J, Mikhail G, Yacoub MH, et al. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol 1998;185:313-8.
100. Hagan G, Pepke-Zaba J. Pulmonary hypertension, nitric oxide and nitric oxide-releasing compounds. Expert Rev Respir Med 2011;5:163-71.
101. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37:741-5.
102. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002;105:1672-8.
103. Gangopahyay A, Oran M, Bauer EM, Wertz JW, Comhair SA, Erzurum SC, et al. Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation. J Biol Chem 2011;286:33134-40.
104. Forrest IA, Small T, Corris PA. Effect of nebulized epoprostenol (prostacyclin) on exhaled nitric oxide in patients with pulmonary hypertension due to congenital heart disease and in normal controls. Clin Sci (Lond) 1999;97:99-102.
105. Rolla G, Colagrande P, Brussino L, Bucca C, Bertero MT, Caligaris-Cappio F. Exhaled nitric oxide and pulmonary response to iloprost in systemic sclerosis with pulmonary hypertension. Lancet 1998;351:1491-2.
106. Machado RF, Londhe Nerkar MV, Dweik RA, Hammel J, Janocha A, Pyle J, et al. Nitric oxide and pulmonary arterial pressures in pulmonary hypertension. Free Radic Biol Med 2004;37:1010-7.
107. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993;91:1367-73.
108. Millatt LJ, Whitley GS, Li D, Leiper JM, Siragy HM, Carey RM, et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 2003;108:1493-8.
109. Kielstein JT, Bode-Boger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005;25:1414-8.
110. Pullamsetti S, Kiss L, Ghofrani HA, Voswinckel R, Haredza P, Klepetko W, et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J 2005;19:1175-7.
111. Skoro-Sajer N, Mittermayer F, Panzenboeck A, Bonderman D, Sadushi R, Hitsch R, et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2007;176:1154-60.
112. Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, et al. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 2004;18:1746-8.
113. American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912-30.
114. Condorelli P, Shin HW, Aledia AS, Silkoff PE, George SC. A simple technique to characterize proximal and peripheral nitric oxide exchange using constant flow exhalations and an axial diffusion model. J Appl Physiol 2007;102:417-25.
115. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81.
116. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105-11.
117. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S78-84.
118. Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med 2010;104:481-96.
119. Weir EK, Rubin LJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. The acute administration of vasodilators in primary pulmonary hypertension. Experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension. Am Rev Respir Dis 1989;140:1623-30.
120. Post MC, Janssens S, Van de Werf F, Budts W. Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with congenital heart defects and pulmonary arterial hypertension. Eur Heart J 2004;25:1651-6.
121. Skoro-Sajer N, Hack N, Sadushi-Kolici R, Bonderman D, Jakowitsch J, Klepetko W, et al. Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: A pilot study. Circulation 2009;119:298-305.
122. Krasuski RA, Devendra GP, Hart SA, Wang A, Harrison JK, Bashore TM. Response to inhaled nitric oxide predicts survival in patients with pulmonary hypertension. J Card Fail 2011;17:265-71.
123. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57.
124. Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-903.
125. Label approved for REVATIO, NDA # 021845. FDA, 2012. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda.[Last accessed on 2012 April 10].
126. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation 2012;125:324-34.
127. Wharton J, Strange JW, Moller GM, Growcott EJ, Ren X, Franklyn AP, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005;172:105-13.
128. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: Comparison with inhaled nitric oxide. Circulation 2002;105:2398-403.
129. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 2007;116:238-48.
130. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038-47.
131. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991;338:1173-4.
132. Vonbank K, Ziesche R, Higenbottam TW, Stiebellehner L, Petkov V, Schenk P, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax 2003;58:289-93.
133. Channick RN, Newhart JW, Johnson FW, Williams PJ, Auger WR, Fedullo PF, et al. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: An ambulatory delivery system and initial clinical tests. Chest 1996;109:1545-9.
134. Perez-Penate GM, Julia-Serda G, Ojeda-Betancort N, García-Quintana A, Pulido-Duque J, Rodríguez-Pérez A, et al. Long-term inhaled nitric oxide plus phosphodiesterase 5 inhibitors for severe pulmonary hypertension. J Heart Lung Transplant 2008;27:1326-32.
135. Frampton MW, Morrow PE, Cox C, Gibb FR, Speers DM, Utell MJ. Effects of nitrogen dioxide exposure on pulmonary function and airway reactivity in normal humans. Am Rev Respir Dis 1991;143:522-7.
136. Clutton-Brock J. Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth 1967;39:388-92.
137. Miller OI, Tang SF, Keech A, Celermajer DS. Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide. Lancet 1995;346:51-2.
138. Christenson J, Lavoie A, O’Connor M, Bhorade S, Pohlman A, Hall JB. The incidence and pathogenesis of cardiopulmonary deterioration after abrupt withdrawal of inhaled nitric oxide. Am J Respir Crit Care Med 2000;161:1443-9.
139. Label for INOMAX, NDA # 020845. U.S. Food and Drug Administration. 2010. Accessed from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. [Last accessed on 2012, April 10].
140. Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): A randomised controlled trial. Lancet 2010;376:346-54.
141. Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005;353:13-22.
142. Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P, et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 2006;40:295-302.
143. Hunter CJ, Dejam A, Blood AB, Shields H, Kim-Shapiro DB, Machado RF, et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 2004;10:1122-7.
144. Ingram TE, Pinder AG, Bailey DM, Fraser AG, James PE. Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite. Am J Physiol Heart Circ Physiol 2010;298:H331-9.
145. Brandler MD, Powell SC, Craig DM, Quick G, McMahon TJ, Goldberg RN, et al. A novel inhaled organic nitrate that affects pulmonary vascular tone in a piglet model of hypoxia-induced pulmonary hypertension. Pediatr Res 2005;58:531-6.
146. Keefer LK, Nims RW, Davies KM, Wink DA. “NONOates” (1-substituted diazen-1-ium-1,2-diolates) as nitric oxide donors: Convenient nitric oxide dosage forms. Methods Enzymol 1996;268:281-93.
147. Hampl V, Tristani-Firouzi M, Hutsell TC, Archer SL. Nebulized nitric oxide/nucleophile adduct reduces chronic pulmonary hypertension. Cardiovasc Res 1996;31:55-62.
148. Young KC, Ladino J, Navarrete C, Dabrowska K, Hehre D, Bancalari E, et al. The effect of a nebulized NO donor, DPTA/NO, on acute hypoxic pulmonary hypertension in newborn piglets. Biol Neonate 2004;85:195-202.
149. Lam CF, Van Heerden PV, Blott J, Roberts B, Ilett KF. The selective pulmonary vasodilatory effect of inhaled DETA/NO, a novel nitric oxide donor, in ARDS-a pilot human trial. J Crit Care 2004;19:48-53.
150. Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Müller D, Schlüter KD, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008;32:881-91.
151. Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: A phase II study. Eur Respir J 2010;36:792-9.
152. Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 2011;20:567-76.
153. Ou ZJ, Wei W, Huang DD, Luo W, Luo D, Wang ZP, et al. L-arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats. Am J Physiol Endocrinol Metab 2010;298:E1131-9.
154. Howell K, Costello CM, Sands M, Dooley I, McLoughlin P. L-Arginine promotes angiogenesis in the chronically hypoxic lung: A novel mechanism ameliorating pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2009;296:L1042-50.
155. Mitani Y, Maruyama K, Sakurai M. Prolonged administration of L-arginine ameliorates chronic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 1997;96:689-97.
156. Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, 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.
157. Morris CR, Morris SM Jr., Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, et al. Arginine therapy: A new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168:63-9.
158. Ananthakrishnan M, Barr FE, Summar ML, Smith HA, Kaplowitz M, Cunningham G, et al. L-Citrulline ameliorates chronic hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiol Lung Cell Mol Physiol 2009;297:L506-11.
159. Smith HA, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, et al. Nitric oxide precursors and congenital heart surgery: A randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg 2006;132:58-65.
160. Nakayama DK, Geller DA, Di Silvio M, Bloomgarden G, Davies P, Pitt BR, et al. Tetrahydrobiopterin synthesis and inducible nitric oxide production in pulmonary artery smooth muscle. Am J Physiol 1994;266:L455-60.
161. Gross SS, Levi R. Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem 1992;267:25722-9.
162. Raman CS, Li H, Martasek P, Kral V, Masters BS, Poulos TL. Crystal structure of constitutive endothelial nitric oxide synthase: A paradigm for pterin function involving a novel metal center. Cell 1998;95:939-50.
163. Venema RC, Ju H, Zou R, Ryan JW, Venema VJ. Subunit interactions of endothelial nitric-oxide synthase. Comparisons to the neuronal and inducible nitric-oxide synthase isoforms. J Biol Chem 1997;272:1276-82.
164. Robbins IM, Hemnes AR, Gibbs JS, Christman BW, Howard L, Meehan S, et al. Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension. Exp Lung Res 2011;37:26-34.
165. Steinhorn RH, Albert G, Swartz DD, Russell JA, Levine CR, Davis JM. Recombinant human superoxide dismutase enhances the effect of inhaled nitric oxide in persistent pulmonary hypertension. Am J Respir Crit Care Med 2001;164:834-9.
166. Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: A pilot randomized controlled trial. J Am Coll Cardiol 2007;49:1566-71.
167. Deng W, Bivalacqua TJ, Champion HC, Hellstrom WJ, Murthy SN, Kadowitz PJ. Gene therapy techniques for the delivery of endothelial nitric oxide synthase to the lung for pulmonary hypertension. Methods Mol Biol 2010;610:309-21.
168. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: Efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005; 96:442-50.
169. Kanki-Horimoto S, Horimoto H, Mieno S, Kishida K, Watanabe F, Furuya E, et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation 2006;114:I181-5.
170. Janssens SP, Bloch KD, Nong Z, Gerard RD, Zoldhelyi P, Collen D. Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. J Clin Invest 1996;98:317-24.
171. Budts W, Pokreisz P, Nong Z, Van Pelt N, Gillijns H, Gerard R, et al. Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 2000;102:2880-5.