1887
Volume 2014, Issue 4
  • ISSN: 2305-7823
  • EISSN:

Abstract

Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertension.

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2015-03-01
2024-04-16
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References

  1. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976; 263::663665.
    [Google Scholar]
  2. Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin x) which relaxes strips of mesenteric and coeliac ateries and inhibits platelet aggregation. Prostaglandins. 1976; 12::897913.
    [Google Scholar]
  3. Whittaker N, Bunting S, Salmon J, Moncada S, Vane JR, Johnson RA, Morton DR, Kinner JH, Gorman RR, McGuire JC, Sun FF. The chemical structure of prostaglandin x (prostacyclin). Prostaglandins. 1976; 12::915928.
    [Google Scholar]
  4. Moncada S, Herman AG, Higgs EA, Vane JR. Differential formation of prostacyclin (pgx or pgi2) by layers of the arterial wall. An explanation for the anti-thrombotic properties of vascular endothelium. Thromb Res. 1977; 11::323344.
    [Google Scholar]
  5. Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J. 1989; 259::315324.
    [Google Scholar]
  6. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992; 327::7075.
    [Google Scholar]
  7. 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. Am J Respir Crit Care Med. 1999; 159::19251932.
    [Google Scholar]
  8. Gubrij IB, Martin SR, Pangle AK, Kurten R, Johnson LG. Attenuation of monocrotaline-induced pulmonary hypertension by luminal adeno-associated virus serotype 9 gene transfer of prostacyclin synthase. Hum Gene Ther. 2014; 25::498505.
    [Google Scholar]
  9. Nagaya N, Yokoyama C, Kyotani S, Shimonishi M, Morishita R, Uematsu M, Nishikimi T, Nakanishi N, Ogihara T, Yamagishi M, Miyatake K, Kaneda Y, Tanabe T. Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats. Circulation. 2000; 102::20052010.
    [Google Scholar]
  10. Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, Alger LA, Tuder RM, Voelkel NF. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest. 1999; 103::15091515.
    [Google Scholar]
  11. Zhou L, Chen Z, Vanderslice P, So SP, Ruan KH, Willerson JT, Dixon RA. Endothelial-like progenitor cells engineered to produce prostacyclin rescue monocrotaline-induced pulmonary arterial hypertension and provide right ventricle benefits. Circulation. 2013; 128::982994.
    [Google Scholar]
  12. Takemiya K, Kai H, Yasukawa H, Tahara N, Kato S, Imaizumi T. Mesenchymal stem cell-based prostacyclin synthase gene therapy for pulmonary hypertension rats. Basic Res Cardiol. 2010; 105::409417.
    [Google Scholar]
  13. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. Membrane transporters in drug development. Nat Rev Drug Discov. 2010; 9::215236.
    [Google Scholar]
  14. Warner TD, Mitchell JA. Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: As easy as abc? Proc Natl Acad Sci U S A. 2003; 100::91089110.
    [Google Scholar]
  15. Hara Y, Sassi Y, Guibert C, Gambaryan N, Dorfmuller P, Eddahibi S, Lompre AM, Humbert M, Hulot JS. Inhibition of mrp4 prevents and reverses pulmonary hypertension in mice. J Clin Invest. 2011; 121::28882897.
    [Google Scholar]
  16. Hewer RC, Sala-Newby GB, Wu YJ, Newby AC, Bond M. Pka and epac synergistically inhibit smooth muscle cell proliferation. Journal of Molecular and Cellular Cardiology. 2011; 50::8798.
    [Google Scholar]
  17. Murray RS F, Kwon O, Li X, Remillard CV, Thistlethwaite PA, Yuan JX, Insel PA. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A1804 RM. Decreased expression and activity of epac (exchange protein directly activated by camp) in pulmonary arterial hypertension. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A1804 .
  18. Wilson SM, Sheddan NA, Newton R, Giembycz MA. Evidence for a second receptor for prostacyclin on human airway epithelial cells that mediates inhibition of cxcl9 and cxcl10 release. Molecular Pharmacology. 2011; 79::586595.
    [Google Scholar]
  19. Giguere V, Gallant MA, de Brum-Fernandes AJ, Parent JL. Role of extracellular cysteine residues in dimerization/oligomerization of the human prostacyclin receptor. European Journal of Pharmacology. 2004; 494::1122.
    [Google Scholar]
  20. Wilson SJ, Roche AM, Kostetskaia E, Smyth EM. Dimerization of the human receptors for prostacyclin and thromboxane facilitates thromboxane receptor-mediated camp generation. The Journal of Biological Chemistry. 2004; 279::5303653047.
    [Google Scholar]
  21. Smyth EM, Li WH, FitzGerald GA. Phosphorylation of the prostacyclin receptor during homologous desensitization. A critical role for protein kinase c. The Journal of Biological Chemistry. 1998; 273::2325823266.
    [Google Scholar]
  22. Smyth EM, Austin SC, Reilly MP, FitzGerald GA. Internalization and sequestration of the human prostacyclin receptor. The Journal of Biological Chemistry. 2000; 275::3203732045.
    [Google Scholar]
  23. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jobsis MM, Blackburn SD, Shortino D, Crow JW. Primary pulmonary hypertension study G. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996; 334::296301.
    [Google Scholar]
  24. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998; 338::273277.
    [Google Scholar]
  25. Archer SL, Mike D, Crow J, Long W, Weir EK. A placebo-controlled trial of prostacyclin in acute respiratory failure in copd. Chest. 1996; 109::750755.
    [Google Scholar]
  26. Belvisi MG, Mitchell JA. Targeting ppar receptors in the airway for the treatment of inflammatory lung disease. Br J Pharmacol. 2009; 158::9941003.
    [Google Scholar]
  27. Ali FY, Davidson SJ, Moraes LA, Traves SL, Paul-Clark M, Bishop-Bailey D, Warner TD, Mitchell JA. Role of nuclear receptor signaling in platelets: Antithrombotic effects of pparbeta. Faseb J. 2006; 20::326328.
    [Google Scholar]
  28. Ali FY, Egan K, FitzGerald GA, Desvergne B, Wahli W, Bishop-Bailey D, Warner TD, Mitchell JA. Role of prostacyclin versus peroxisome proliferator-activated receptor beta receptors in prostacyclin sensing by lung fibroblasts. Am J Respir Cell Mol Biol. 2006; 34::242246.
    [Google Scholar]
  29. Harrington LS, Moreno L, Reed A, Wort SJ, Desvergne B, Garland C, Zhao L, Mitchell JA. The pparbeta/delta agonist gw0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension. PLoS One. 2010; 5::e9526.
    [Google Scholar]
  30. Li Y, Connolly M, Nagaraj C, Tang B, Balint Z, Popper H, Smolle-Juettner FM, Lindenmann J, Kwapiszewska G, Aaronson PI, Wohlkoenig C, Leithner K, Olschewski H, Olschewski A. Peroxisome proliferator-activated receptor-beta/delta, the acute signaling factor in prostacyclin-induced pulmonary vasodilation. Am J Respir Cell Mol Biol. 2012; 46::372379.
    [Google Scholar]
  31. Kojonazarov B, Luitel H, Sydykov A, Dahal BK, Paul-Clark MJ, Bonvini S, Reed A, Schermuly RT, Mitchell JA. The peroxisome proliferator-activated receptor beta/delta agonist gw0742 has direct protective effects on right heart hypertrophy. Pulm Circ. 2013; 3::926935.
    [Google Scholar]
  32. Liu J, Wang P, Luo J, Huang Y, He L, Yang H, Li Q, Wu S, Zhelyabovska O, Yang Q. Peroxisome proliferator-activated receptor beta/delta activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition. Hypertension. 2011; 57::223230.
    [Google Scholar]
  33. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R. Genetic evidence for high-altitude adaptation in tibet. Science. 2010; 329::7275.
    [Google Scholar]
  34. Galaup A, Gomez E, Souktani R, Durand M, Cazes A, Monnot C, Teillon J, Le Jan S, Bouleti C, Briois G, Philippe J, Pons S, Martin V, Assaly R, Bonnin P, Ratajczak P, Janin A, Thurston G, Valenzuela DM, Murphy AJ, Yancopoulos GD, Tissier R, Berdeaux A, Ghaleh B, Germain S. Protection against myocardial infarction and no-reflow through preservation of vascular integrity by angiopoietin-like 4. Circulation. 2012; 125::140149.
    [Google Scholar]
  35. Sprecher DL, Massien C, Pearce G, Billin AN, Perlstein I, Willson TM, Hassall DG, Ancellin N, Patterson SD, Lobe DC, Johnson TG. Triglyceride: High-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist. Arterioscler Thromb Vasc Biol. 2007; 27::359365.
    [Google Scholar]
  36. Geiger LE, Dunsford WS, Lewis DJ, Brennan C, Liu KC, Newsholme SJ. Rat carcinogenicity study with gw501516, a ppar delta agonist. The Toxicologist, 2009; 108:(1):895(abstract)
    [Google Scholar]
  37. Newsholme SJ, Dunsford WS, Brodie T, Brennan C, Brown M, Geiger LE. Mouse carcinogenicity study with gw501516, a ppar delta agonist. The Toxicologist, 2009; 108:1:896abstract
    [Google Scholar]
  38. Mitchell JA, Warner TD. Cox isoforms in the cardiovascular system: Understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov. 2006; 5::7586.
    [Google Scholar]
  39. Kirkby NS, Lundberg MH, Harrington LS, Leadbeater PD, Milne GL, Potter CM, Al-Yamani M, Adeyemi O, Warner TD, Mitchell JA. Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system. Proc Natl Acad Sci U S A. 2012; 109::1759717602.
    [Google Scholar]
  40. Kirkby NS, Zaiss AK, Urquhart P, Jiao J, Austin PJ, Al-Yamani M, Lundberg MH, MacKenzie LS, Warner TD, Nicolaou A, Herschman HR, Mitchell JA. Lc-ms/ms confirms that cox-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of cox-2 expression. PLoS One. 2013; 8::e69524.
    [Google Scholar]
  41. Liu B, Luo W, Zhang Y, Li H, Zhu N, Huang D, Zhou Y. Involvement of cyclo-oxygenase-1-mediated prostacyclin synthesis in the vasoconstrictor activity evoked by ach in mouse arteries. Exp Physiol. 2012; 97::277289.
    [Google Scholar]
  42. Kirkby NS, Lundberg MH, Wright WR, Warner TD, Paul-Clark MJ, Mitchell JA. Cox-2 protects against atherosclerosis independently of local vascular prostacyclin: Identification of cox-2 associated pathways implicate rgl1 and lymphocyte networks. PLoS One. 2014; 9::e98165.
    [Google Scholar]
  43. Kirkby NS, Chan MV, Lundberg MH, Massey KA, Edmands WM, MacKenzie LS, Holmes E, Nicolaou A, Warner TD, Mitchell JA. Aspirin-triggered 15-epi-lipoxin a4 predicts cyclooxygenase-2 in the lungs of lps-treated mice but not in the circulation: Implications for a clinical test. Faseb J. 2013; 27::39383946.
    [Google Scholar]
  44. Pugliese SC, Poth JM, Fini MA, Olschewski A, Kasmi KCE, Stenmark KR. The role of inflammation in hypoxic pulmonary hypertension: From cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol. 2015; 308:3:L229L252. doi:10.1152/ajplung.00238.2014 .
    [Google Scholar]
  45. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014; 115::165175.
    [Google Scholar]
  46. Cracowski JL, Chabot F, Labarere J, Faure P, Degano B, Schwebel C, Chaouat A, Reynaud-Gaubert M, Cracowski C, Sitbon O, Yaici A, Simonneau G, Humbert M. Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension. Eur Respir J. 2014; 43::915917.
    [Google Scholar]
  47. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010; 122::920927.
    [Google Scholar]
  48. George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes AM, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan JG, Humbert M, Zhao L, Mitchell JA. Evidence for the involvement of type i interferon in pulmonary arterial hypertension. Circ Res. 2014; 114::677688.
    [Google Scholar]
  49. George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. Pharmacology and therapeutic potential of interferons. Pharmacol Ther. 2012; 135::4453.
    [Google Scholar]
  50. Jourdan KB, Evans TW, Lamb NJ, Goldstraw P, Mitchell JA. Autocrine function of inducible nitric oxide synthase and cyclooxygenase-2 in proliferation of human and rat pulmonary artery smooth-muscle cells: Species variation. Am J Respir Cell Mol Biol. 1999; 21::105110.
    [Google Scholar]
  51. Bradbury DA, Newton R, Zhu YM, Stocks J, Corbett L, Holland ED, Pang LH, Knox AJ. Effect of bradykinin, tgf-beta1, il-1beta, and hypoxia on cox-2 expression in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002; 283::L717L725.
    [Google Scholar]
  52. Yang X, Sheares KK, Davie N, Upton PD, Taylor GW, Horsley J, Wharton J, Morrell NW. Hypoxic induction of cox-2 regulates proliferation of human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2002; 27::688696.
    [Google Scholar]
  53. Sheares KK, Jeffery TK, Long L, Yang X, Morrell NW. Differential effects of tgf-beta1 and bmp-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2004; 287::L919L927.
    [Google Scholar]
  54. Cathcart MC, Tamosiuniene R, Chen G, Neilan TG, Bradford A, O'Byrne KJ, Fitzgerald DJ, Pidgeon GP. Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis. J Pharmacol Exp Ther. 2008; 326::5158.
    [Google Scholar]
  55. Fredenburgh LE, Liang OD, Macias AA, Polte TR, Liu X, Riascos DF, Chung SW, Schissel SL, Ingber DE, Mitsialis SA, Kourembanas S, Perrella MA. Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation. 2008; 117::21142122.
    [Google Scholar]
  56. Rakotoniaina Z, Guerard P, Lirussi F, Rochette L, Dumas M, Goirand F, Bardou M. Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat. Naunyn Schmiedebergs Arch Pharmacol. 2008; 378::241251.
    [Google Scholar]
  57. Hossmann V, Auel H, Rucker W, Schror K. Prolonged infusion of prostacyclin in patients with advanced stages of peripheral vascular disease: A placebo-controlled cross-over study. Klinische Wochenschrift. 1984; 62::11081114.
    [Google Scholar]
  58. Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, Palevsky HI, Rich S, Sood N, Rosenzweig EB, Trow TK, Yung R, Elliott CG, Badesch DB. Pharmacologic therapy for pulmonary arterial hypertension in adults: Chest guideline and expert panel report. Chest. 2014; 146::449475.
    [Google Scholar]
  59. Butrous G. The role of phosphodiesterase inhibitors in the management of pulmonary vascular diseases. Global Cardiology Science and Practice. 2014; 42:. http://dx.doi.org/10.5339/gcsp.2014.42 .
    [Google Scholar]
  60. Nguyen H, Amanullah AM. Therapeutic potentials of phosphodiesterase-5 inhibitors in cardiovascular disease. Reviews in Cardiovascular Medicine. 2014; 15::158167.
    [Google Scholar]
  61. Chester AH, Yacoub MH. The role of endothelin-1 in pulmonary arterial hypertension. Global Cardiology Science & Practice. 2014; 2014::6278.
    [Google Scholar]
  62. Kirkby NS, Lundberg MH, Chan MV, Vojnovic I, Solomon AB, Emerson M, Mitchell JA, Warner TD. Blockade of the purinergic p2y12 receptor greatly increases the platelet inhibitory actions of nitric oxide. Proc Natl Acad Sci U S A. 2013; 110::1578215787.
    [Google Scholar]
  63. George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes AM, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan JG, Humbert M, Zhao L, Mitchell JA. Evidence for the involvement of type i interferon in pulmonary arterial hypertension. Circ Res. 2014; 114::677688.
    [Google Scholar]
  64. Lavoie JR, Ormiston ML, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW, Stewart DJ. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation. 2014; 129::21252135.
    [Google Scholar]
  65. Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, Degano B, Bonderman D, Kurzyna M, Efficace M, Giorgino R, Lang IM. Selexipag: An oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012; 40::874880.
    [Google Scholar]
  66. Actelion. Selexipag (ACT-293987) in Pulmonary Arterial Hypertension, GRIPHON Trial. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2015 Feb 24]. Available from https://clinicaltrials.gov/ct2/show/nct01106014. NLM Identifier: NCT01106014.
  67. Feldman J, Im Y, Gill K. Oral treprostinil diethanolamine for pulmonary arterial hypertension. Expert Review of Clinical Pharmacology. 2015; 8::5560.
    [Google Scholar]
  68. Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, Kotlyar E, McSwain CS, Laliberte K, Arneson C, Rubin LJ, Team F-CS. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the freedom-c2 study): A randomized controlled trial. Chest. 2013; 144::952958.
    [Google Scholar]
  69. Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, Badesch DB, Frost AE, Shapiro SM, Laliberte K, Sigman J, Arneson C, Galie N. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the freedom-c study): A randomized controlled trial. Chest. 2012; 142::13831390.
    [Google Scholar]
  70. Ryan SM, Brayden DJ. Progress in the delivery of nanoparticle constructs: Towards clinical translation. Current Opinion in Pharmacology. 2014; 18C::120128.
    [Google Scholar]
  71. Mosgoeller W, Prassl R, Zimmer A. Nanoparticle-mediated treatment of pulmonary arterial hypertension. Methods in Enzymology. 2012; 508::325354.
    [Google Scholar]
  72. Ruan CH, Dixon RA, Willerson JT, Ruan KH. Prostacyclin therapy for pulmonary arterial hypertension. Texas Heart Institute Journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 2010; 37::391399.
    [Google Scholar]
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