Skip to main content
Log in

The Role of the NO Axis and its Therapeutic Implications in Pulmonary Arterial Hypertension

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature leading to vasoconstriction and remodeling of the pulmonary arteries. The resulting increase in the right ventricular afterload leads to right ventricular failure and death. The treatment options are limited, expensive and associated with significant side effects. The nitric oxide (NO) pathway in the pulmonary circulation provides several targets for the development of new therapies for this disease. However, the NO pathway is modulated at multiple levels including transcription and expression of the NO synthase gene, regulation of the NO synthase activity, regulation of the production of cyclic guanomonophosphate (cGMP) by phosphodiesterases, postsynthetic oxidation of NO, etc. This makes the study of the role of the NO pathway very difficult, unless one uses multiple complementary techniques. Furthermore, there are significant differences between the pulmonary and the systemic circulation which make extrapolation of data from one circulation to the other very difficult. In addition, the role of NO in the development of pulmonary hypertension varies among different models of the disease. This paper reviews the role of the NO pathway in both the healthy and diseased pulmonary circulation and in several animal models and human forms of the disease. It focuses on the role of recent therapies that target the NO pathway, including L-Arginine, inhaled NO, the phosphodiesterase inhibitor sildenafil and gene therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Michelakis ED, Archer SL, Weir EK. Acute hypoxic pulmonary vasoconstriction: A model of oxygen sensing. Physiol Res 1995;44:361-367.

    Google Scholar 

  2. Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: The tale of two channels. FASEB J 1995;9:183-189.

    Google Scholar 

  3. Michelakis ED, Hampl V, Nsair A, Wu X, Harry G, Haromy A, Gurtu R, Archer SL. Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ Res 2002;90:1307-1315.

    Google Scholar 

  4. Wolin MS. Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol 2000;20:1430-1442.

    Google Scholar 

  5. Archer SL. Measurement of nitric oxide in biological models. FASEB J 1993;7:349-360.

    Google Scholar 

  6. Michelakis E TD-X, Djaballah K, Souil E, Archer S. Measurement of NO and NO synthase activity. In: Mathie RT, Griffith TM, eds. Hemodynamic Effects of NO. Singapore: World Scientific, 1999:161-183.

    Google Scholar 

  7. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-2012.

    Google Scholar 

  8. Sherman TS, Chen Z, Yuhanna IS, Lau KS, Margraf LR, Shaul PW. Nitric oxide synthase isoform expression in the developing lung epithelium. Am J Physiol 1999;276:L383-L390.

    Google Scholar 

  9. Rairigh RL, Le Cras TD, Ivy DD, Kinsella JP, Richter G, Horan MP, Fan ID, Abman SH. Role of inducible nitric oxide synthase in regulation of pulmonary vascular tone in the late gestation ovine fetus. J Clin Invest 1998;101:15-21.

    Google Scholar 

  10. Boulanger CM, Heymes C, Benessiano J, Geske RS, Levy BI, Vanhoutte PM. Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: Activation by angiotensin II in hypertension [In Process Citation]. Circ Res 1998;83:1271-1278.

    Google Scholar 

  11. 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 USA 1994;91:7583-7587.

    Google Scholar 

  12. Robertson BE, Schubert R, Hescheler J, Nelson M. cGMPdependent protein kinase activates Ca-activated K channels in cerebral artery smooth muscle cells. Am J Physiol 1993;265:C299-C303.

    Google Scholar 

  13. Archer SL, Rusch NJ (eds). Potassium Channels in Cardiovascular Biology, 1st edn. New York: Kluwer Academic/Plenum Publishers, 2001.

    Google Scholar 

  14. Archer SL, Weir EK, Reeve HL, Michelakis E. Molecular identification of O2 sensors and O2-sensitive potassium channels in the pulmonary circulation. Adv Exp Med Biol 2000;475:219-240.

    Google Scholar 

  15. Murad F. The 1996 Albert Lasker Medical Research Awards. Signal transduction using nitric oxide and cyclic guanosine monophosphate. JAMA 1996;276:1189-1192.

    Google Scholar 

  16. Wu X, Haystead TA, Nakamoto RK, Somlyo AV, Somlyo AP. Acceleration of myosin light chain dephosphorylation and relaxation of smooth muscle by telokin. Synergism with cyclic nucleotide-activated kinase. J Biol Chem 1998;273:11362-11369.

    Google Scholar 

  17. Michelakis ED, Weir EK. The pathobiology of pulmonary hypertension. Smooth muscle cells and ion channels. Clin Chest Med 2001;22:419-432.

    Google Scholar 

  18. Weir EK, Archer SL. Hypoxic pulmonary vasoconstriction: A tale of two channels. FASEB, in press.

  19. Michelakis ED, Weir EK. Anorectic drugs and pulmonary hypertension from the bedside to the bench. Am J Med Sci 2001;321:292-299.

    Google Scholar 

  20. Yuan X-J, Goldman W, Tod ML, Rubin LJ, Blaustein MP. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol 1993;264:L116-L123.

    Google Scholar 

  21. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105:244-250.

    Google Scholar 

  22. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K+ channel gene transcription in primary pulmonary hypertension [letter]. Lancet 1998;351:726-727.

    Google Scholar 

  23. Hampl V, Herget J. Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol Rev 2000;80:1337-1372.

    Google Scholar 

  24. Kawai N, Bloch DB, Filippov G, Rabkina D, Suen HC, Losty PD, Janssens SP, Zapol WM, de la Monte S, Bloch KD. Constitutive endothelial nitric oxide synthase gene expression is regulated during lung development. Am J Physiol 1995;268:L589-L595.

    Google Scholar 

  25. Le Cras TD, Xue C, Rengasamy A, Johns RA. Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung. Am J Physiol 1996;270:L164-L170.

    Google Scholar 

  26. Tyler RC, Muramatsu M, Abman SH, Stelzner TJ, Rodman DM, Bloch KD, McMurtry IF. Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension. Am J Physiol 1999;276:L297-L303.

    Google Scholar 

  27. Xue C, Rengasamy A, Le Cras TD, Koberna PA, Dailey GC, Johns RA. Distribution of NOS in normoxic vs. hypoxic rat lung: Upregulation of NOS by chronic hypoxia. Am J Physiol 1994;267:L667-L678.

    Google Scholar 

  28. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, Stamler JS. Nitric oxide synthase in human and rat lung: Immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 1993;9:371-377.

    Google Scholar 

  29. Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC, Bevan JA, Fishman MC, Zapol WM. Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS3) gene. Circ Res 1997;81:34-41.

    Google Scholar 

  30. Steinhorn RH, Millard SL, Morin FC, III. Persistent pulmonary hypertension of the newborn. Role of nitric oxide and endothelin in pathophysiology and treatment. Clin Perinatol 1995;22:405-428.

    Google Scholar 

  31. Steinhorn RH, Morin FC, III, Fineman JR. Models of persistent pulmonary hypertension of the newborn (PPHN) and the role of cyclic guanosine monophosphate (GMP) in pulmonary vasorelaxation. Semin Perinatol 1997;21:393- 408.

    Google Scholar 

  32. Archer S, Rich S. Primary pulmonary hypertension: A vascular biology and translational research "work in progress." Circulation 2000;102:2781-2791.

    Google Scholar 

  33. Higenbottam T, Cremona G. Acute and chronic hypoxic pulmonary hypertension. Eur Respir J 1993;6:1207-1212.

    Google Scholar 

  34. Schultze AE, Roth RA. Chronic pulmonary hypertension- the monocrotaline model and involvement of the hemostatic system. J Toxicol Environ Health B Crit Rev 1998;1:271-346.

    Google Scholar 

  35. Molteni A, Ward WF, Ts'ao CH, Port CD, Solliday NH. Monocrotaline-induced pulmonary endothelial dysfunction in rats. Proc Soc Exp Biol Med 1984;176:88-94.

    Google Scholar 

  36. van Suylen RJ, Smits JF, Daemen MJ. Pulmonary artery remodeling differs in hypoxia-and monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med 1998;157:1423-1428.

    Google Scholar 

  37. Le Cras TD, Kim DH, Gebb S, Markham NE, Shannon JM, Tuder RM, Abman SH. Abnormal lung growth and the development of pulmonary hypertension in the Fawn-Hooded rat. Am J Physiol 1999;277:L709-L718.

    Google Scholar 

  38. Le Cras TD, Kim DH, Markham NE, Abman AS. Early abnormalities of pulmonary vascular development in the Fawn-Hooded rat raised at Denver's altitude. Am J Physiol Lung Cell Mol Physiol 2000;279:L283-L291.

    Google Scholar 

  39. Stelzner T, Hofmann TA, Brown D, Deng A, Jacob HJ. Genetic determinants of pulmonary hypertension in fawn-hooded rats. Chest 1997;111:96S.

    Google Scholar 

  40. Resta TC, Gonzales RJ, Dail WG, Sanders TC, Walker BR. Selective upregulation of arterial endothelial nitric oxide synthase in pulmonary hypertension. Am J Physiol 1997;272:H806-H813.

    Google Scholar 

  41. Resta TC, O'Donaughy TL, Earley S, Chicoine LG, Walker BR. Unaltered vasoconstrictor responsiveness after iNOS inhibition in lungs from chronically hypoxic rats. Am J Physiol 1999;276:L122-L130.

    Google Scholar 

  42. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-221.

    Google Scholar 

  43. Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:1642-1644.

    Google Scholar 

  44. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. AmJ Respir Crit Care Med 1999;159:1925-1932.

    Google Scholar 

  45. Rengasamy A, Johns RA. Characterization of endothelium-derived relaxing factor/nitric oxide synthase from bovine cerebellum and mechanism of modulation The Role of NO in Pulmonary Hypertension 19 by high and low oxygen tensions. J Pharmacol Exp Ther 1991;259:310-316.

    Google Scholar 

  46. Rengasamy A, Johns RA. Determination ofKmfor oxygen of nitric oxide synthase isoforms. J Pharmacol Exp Ther 1996;276:30-33.

    Google Scholar 

  47. Isaacson TC, Hampl V, Weir EK, Nelson DP, Archer SL. Increased endothelium-derived NO in hypertensive pulmonary circulation of chronically hypoxic rats. J Appl Physiol 1994;76:933-940.

    Google Scholar 

  48. Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol 1998;275:L818-L826.

    Google Scholar 

  49. Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 1995;182:1683-1693.

    Google Scholar 

  50. Forstermann U, Boissel JP, Kleinert H. Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J 1998;12:773-790.

    Google Scholar 

  51. Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 1993;92:99-104.

    Google Scholar 

  52. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, Marumo F. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993;91:1367-1373.

    Google Scholar 

  53. Wong J, Vanderford PA, Winters J, Soifer SJ, Fineman JR. Endothelin B receptor agonists produce pulmonary vasodilation in intact newborn lambs with pulmonary hypertension. J Cardiovasc Pharmacol 1995;25:207-215.

    Google Scholar 

  54. Frasch HF, Marshall C, Marshall BE. Endothelin-1 is elevated in monocrotaline pulmonary hypertension. Am J Physiol 1999;276:L304-L310.

    Google Scholar 

  55. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-1739.

    Google Scholar 

  56. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464- 469.

    Google Scholar 

  57. Blumberg FC, Wolf K, Sandner P, Lorenz C, Riegger GA, Pfeifer M. The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs. Am J Physiol Lung Cell Mol Physiol 2001;280:L258-L263.

    Google Scholar 

  58. Sharma RV, Tan E, Fang S, Gurjar MV, Bhalla RC. NOS gene transfer inhibits expression of cell cycle regulatory molecules in vascular smooth muscle cells. Am J Physiol 1999;276:H1450-H1459.

    Google Scholar 

  59. 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;83:1774-1777.

    Google Scholar 

  60. Fukuo K, Hata S, Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, Morimoto S, Ogihara T. Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 1996;27:823-826.

    Google Scholar 

  61. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH. Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. Circ Res 1996;79:748-756.

    Google Scholar 

  62. Duchen MR. Mitochondria and Ca(2+) in cell physiology and pathophysiology. Cell Calcium 2000;28:339-348.

    Google Scholar 

  63. Fagan KA, Fouty BW, Tyler RC, Morris KG, Jr., Hepler LK, Sato K, LeCras TD, Abman SH, Weinberger HD, Huang PL, McMurtry IF, Rodman DM. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 1999;103:291-299.

    Google Scholar 

  64. Quinlan TR, Li D, Laubach VE, Shesely EG, Zhou N, Johns RA. eNOS-deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 2000;279:L641-L650.

    Google Scholar 

  65. Beckman JS. ?OONO: Rebounding from nitric oxide. Circ Res 2001;89:295-297.

    Google Scholar 

  66. Zou M-H, Ullrich V. Peroxynitrite formed by simultaneous generation of NO and suproxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Lett 1996;382:101-104.

    Google Scholar 

  67. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296-302.

    Google Scholar 

  68. Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM. Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy. Circ Res 2001;89:357-364.

    Google Scholar 

  69. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;335:609-616.

    Google Scholar 

  70. Weir EK, Reeve HL, Huang J, Michelakis E, Nelson DP, Hampl V, Archer SL. Anorexic agents Aminorex, Fenfluramine and Dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 1996;94:2216-2220.

    Google Scholar 

  71. Michelakis ED, Weir EK, Nelson DP, Reeve HL, Tolarova S, Archer SL. Dexfenfluramine elevates systemic blood pressure by inhibiting potassium currents in vascular smooth muscle cells. J Pharmacol Exp Ther 1999;291:1143-1149.

    Google Scholar 

  72. Archer S, Djaballah K, Humbert M, Weir E, Fartoukh M, Dall'Ava-Santucci J, Mercier J-C, Simonneau G, Dinh-Xuan A. Nitric oxide deficiency in fenfluramine-and dexfenfluramine-induced pulmonary hypertension. Am J Respir Crit Care Med 1998;158:4:1061-1067.

    Google Scholar 

  73. 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.

    Google Scholar 

  74. Barst R. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest 1986;89:497-503.

    Google Scholar 

  75. Lunn RJ. Inhaled nitric oxide therapy. Mayo Clin Proc 1995;70:247-255.

    Google Scholar 

  76. Steudel W, Hurford WE, Zapol WM. Inhaled nitric oxide: Basic biology and clinical applications. Anesthesiology 1999;91:1090-1121.

    Google Scholar 

  77. Ricciardi MJ, Knight BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension: A safe and effective agent for predicting response to nifedipine. J Am Coll Cardiol 1998;32:1068-1073.

    Google Scholar 

  78. Rich S. Primary Pulmonary Hypertension: Executive Summary from the World Symposium-Primary Pulmonary Hypertension 1998. In: World Health Organization, 1998.

  79. Sitbon O, Humbert M, Jagot JL, Taravella O, Fartoukh M, Parent F, Herve P, Simonneau G. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998;12:265-270.

    Google Scholar 

  80. 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;338:1173-1174.

    Google Scholar 

  81. Pagano D, Townend JN, Horton R, Smith C, Clutton-Brock T, Bonser RS. A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation. Eur J Cardiothorac Surg 1996;10:1120-1126.

    Google Scholar 

  82. Adatia I, Perry S, Landzberg M, Moore P, Thompson JE, Wessel DL. Inhaled nitric oxide and hemodynamic evaluation of patients with pulmonary hypertension before transplantation. J Am Coll Cardiol 1995;25:1656-1664.

    Google Scholar 

  83. Abman SH. Pathogenesis and treatment of neonatal and postnatal pulmonary hypertension. Curr Opin Pediatr 1994;6:239-247.

    Google Scholar 

  84. Channick RN, Rubin LJ. New and experimental therapies for pulmonary hypertension. Clin Chest Med 2001;22:539-545.

    Google Scholar 

  85. Roberts JD, Jr., Chiche JD, Weimann J, Steudel W, Zapol WM, Bloch KD. Nitric oxide inhalation decreases pulmonary artery remodeling in the injured lungs of rat pups. Circ Res 2000;87:140-145.

    Google Scholar 

  86. Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994;90:2780-2785.

    Google Scholar 

  87. Semigran MJ, Cockrill BA, Kacmarek R, Thompson BT, Zapol WM, Dec GW, Fifer MA. Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol 1994;24:982-988.

    Google Scholar 

  88. Bocchi EA, Bacal F, Auler Junior JO, Carmone MJ, Bellotti G, Pileggi F. Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure. Am J Cardiol 1994;74:70-72.

    Google Scholar 

  89. Preston IR, Klinger JR, Houtchens J, Nelson D, Mehta S, Hill NS. Pulmonary edema caused by inhaled nitric oxide therapy in two patients with pulmonary hypertension associated with the CREST syndrome. Chest 2002;121:656- 659.

    Google Scholar 

  90. 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;105:2398-2403.

    Google Scholar 

  91. Miller OI, Tang SF, Keech A, Celermajer DS. Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide [letter]. Lancet 1995;346:51-52.

    Google Scholar 

  92. Sheehy AM, Burson MA, Black SM. Nitric oxide exposure inhibits endothelialNOSactivity but not gene expression: A role for superoxide. Am J Physiol 1998;274:L833-L841.

    Google Scholar 

  93. Black SM, Heidersbach RS, McMullan DM, Bekker JM, Johengen MJ, Fineman JR. Inhaled nitric oxide inhibits NOS activity in lambs: A potential mechanism for rebound pulmonary hypertension. Am J Physiol 1999;277:H1849-H1856.

    Google Scholar 

  94. McMullan DM, Bekker JM, Johengen MJ, Hendricks-Munoz K, Gerrets R, Black SM, Fineman JR. Inhaled nitric oxide-induced rebound pulmonary hypertension: Role for endothelin-1. Am J Physiol Heart Circ Physiol 2001;280:H777-H785.

    Google Scholar 

  95. Budts W, Pokreisz P, Nong Z, Van Pelt N, Gillijns H, Gerard R, Lyons R, Collen D, Bloch KD, Janssens S. Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 2000;102:2880-2885.

    Google Scholar 

  96. 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;98:317-324.

    Google Scholar 

  97. Campbell AI, Kuliszewski MA, Stewart DJ. Cellbased gene transfer to the pulmonary vasculature: Endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension [see comments]. Am J Respir Cell Mol Biol 1999;21:567-575.

    Google Scholar 

  98. Rector TS, Bank AJ, Mullen KA, Tschumperlin LK, Sih R, Pillai K, Kubo SH. Randomized, double-blind, placebocontrolled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996;93:2135-2141.

    Google Scholar 

  99. Mitani Y, Maruyama K, Sakurai M. Prolonged administration of L-arginine ameliorates chronic pulmonary hypertension and pulmonary vascular remodeling in rats [see comments]. Circulation 1997;96:689-697.

    Google Scholar 

  100. Mehta S, Stewart DJ, Langleben D, Levy RD. Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation 1995;92:1539-1545.

    Google Scholar 

  101. Mehta S, Stewart DJ, Levy RD. The hypotensive effect of L-arginine is associated with increased expired nitric oxide in humans. Chest 1996;109:1550-1555.

    Google Scholar 

  102. Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, Ueno K, Nakanishi N, Yamagishi M, Miyatake K. 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;163:887-891.

    Google Scholar 

  103. Gibson A. Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil. Eur J Pharmacol 2001;411:1-10.

    Google Scholar 

  104. Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD. Cyclic-GMP-binding, cyclic-GMPspecific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr Res 1998;43:163-168.

    Google Scholar 

  105. Cheitlin MD, Hutter AM, Jr., Brindis RG, Ganz P, Kaul S, Russell RO, Jr., Zusman RM. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/ American Heart Association. J Am Coll Cardiol 1999;33:273-282.

    Google Scholar 

  106. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342.

    Google Scholar 

  107. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, Bohm M, Sybrecht GW. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218-1222.

    Google Scholar 

  108. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001;104:424-428.

    Google Scholar 

  109. Holzmann A, Manktelow C, Weimann J, Bloch KD, Zapol WM. Inhibition of lung phosphodiesterase improves responsiveness to inhaled nitric oxide in isolated-perfused lungs from rats challenged with endotoxin. Intensive Care Med 2001;27:251-257.

    Google Scholar 

  110. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, Clark MW, Winkler JD, Bloch KD, Zapol WM. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001;29:1000-1005.

    Google Scholar 

  111. Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM, Kass DA. Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J 2001;15:1718-1726.

    Google Scholar 

  112. Phillips BG, Kato M, Pesek CA, Winnicki M, Narkiewicz K, Davison D, Somers VK. Sympathetic activation by sildenafil. Circulation 2000;102:3068-3073.

    Google Scholar 

  113. Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000;342:1622-1626.

    Google Scholar 

  114. Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM, Rosen RC. On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 2001;13:2-9.

    Google Scholar 

  115. Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E, Bandel, The Vardenafil Study Group T. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: The first at-home clinical trial. Int J Impot Res 2001;13:192-199.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Evangelos D. Michelakis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michelakis, E.D. The Role of the NO Axis and its Therapeutic Implications in Pulmonary Arterial Hypertension. Heart Fail Rev 8, 5–21 (2003). https://doi.org/10.1023/A:1022150819223

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022150819223

Navigation