Skip to main content
Log in

Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension

Advances in Therapy Aims and scope Submit manuscript

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.

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

References

  1. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–S54.

    Article  PubMed  Google Scholar 

  2. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349.

    PubMed  Google Scholar 

  3. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54:S10–S19.

    Article  PubMed  Google Scholar 

  4. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S20–S31.

    Article  PubMed  Google Scholar 

  5. Wharton J, Strange JW, Moller GM, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med. 2005;172:105–113.

    Article  PubMed  Google Scholar 

  6. Corbin JD, Beasley A, Blount MA, Francis SH. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun. 2005;334:930–938.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol. 2005;100:131–138.

    Article  CAS  PubMed  Google Scholar 

  10. Rabe KF, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol. 1994;266:L536–L543.

    CAS  PubMed  Google Scholar 

  11. Giordano D, De Stefano ME, Citro G, Modica A, Giorgi M. Expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in mouse tissues and cell lines using an antibody against the enzyme amino-terminal domain. Biochim Biophys Acta. 2001;16:1527–1539.

    Google Scholar 

  12. Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol. 1998;275:L931–L941.

    CAS  PubMed  Google Scholar 

  13. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732–1739.

    Article  CAS  PubMed  Google Scholar 

  14. Montani D, Souza R, Binkert C, et al. Endothelin-1/endothelin-3 ratio: a potential prognostic factor of pulmonary arterial hypertension. Chest. 2007;131:101–108.

    Article  CAS  PubMed  Google Scholar 

  15. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78–S84.

    Article  PubMed  Google Scholar 

  16. Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest. 1998;114:208S–212S.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Archer SL, Djaballah K, Humbert M, et al. Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension. Am J Respir Crit Care Med. 1998;158:1061–1067.

    CAS  PubMed  Google Scholar 

  19. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006;5:689–702.

    Article  CAS  PubMed  Google Scholar 

  20. Gopal VK, Francis SH, Corbin JD. Allosteric sites of phosphodiesterase-5 (PDE5). A potential role in negative feedback regulation of cGMP signaling in corpus cavernosum. Eur J Biochem. 2001;268:3304–3312.

    Article  CAS  PubMed  Google Scholar 

  21. Schermuly RT, Kreisselmeier KP, Ghofrani HA, et al. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med. 2004;169:39–45.

    Article  PubMed  Google Scholar 

  22. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol. 2004;44:1488–1496.

    CAS  PubMed  Google Scholar 

  23. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract. 2006;60:967–975.

    Article  CAS  PubMed  Google Scholar 

  24. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64:43–50.

    Article  CAS  PubMed  Google Scholar 

  25. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008;48:610–618.

    Article  CAS  PubMed  Google Scholar 

  26. Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of European postmarketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007;30:338–344.

    Article  CAS  PubMed  Google Scholar 

  27. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157.

    Article  CAS  PubMed  Google Scholar 

  28. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521–530.

    PubMed  Google Scholar 

  29. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894–2903.

    Article  CAS  PubMed  Google Scholar 

  30. Jing ZC, Jiang X, Wu BX, et al. Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study. Heart. 2009;95:1531–1536.

    Article  PubMed  Google Scholar 

  31. Guimaraes AC, Malachias MV, Coelho OR, Zilli EC, Luna RL. Use of sildenafil in patients with cardiovascular disease. Arq Bras Cardiol. 1999;73:515–526.

    CAS  PubMed  Google Scholar 

  32. Schermuly RT, Pullamsetti SS, Kwapiszewska G, et al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation. 2007;115:2331–2339.

    Article  CAS  PubMed  Google Scholar 

  33. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425–1436.

    Article  CAS  PubMed  Google Scholar 

  34. Bedard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J. 2009;30:256–265.

    Article  PubMed  Google Scholar 

  35. Price LC, Forrest P, Sodhi V, et al. Use of vasopressin after Caesarean section in idiopathic pulmonary arterial hypertension. Br J Anaesth. 2007;99:552–555.

    Article  CAS  PubMed  Google Scholar 

  36. Lacassie HJ, Germain AM, Valdes G, Fernandez MS, Allamand F, Lopez H. Management of Eisenmenger syndrome in pregnancy with sildenafil and L-arginine. Obstet Gynecol. 2004;103:1118–1120.

    PubMed  Google Scholar 

  37. Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K. Eisenmenger’s syndrome in a 27 week pregnancy - management with bosentan and sildenafil. Ir Med J. 2005;98:87–88.

    CAS  PubMed  Google Scholar 

  38. Schafer S, Ellinghaus P, Janssen W, et al. Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling. Cardiovasc Res. 2009;82:30–39.

    Article  PubMed  Google Scholar 

  39. Bhatia S, Frantz RP, Severson CJ, Durst LA, McGoon MD. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc. 2003;78:1207–1213.

    Article  CAS  PubMed  Google Scholar 

  40. Michelakis ED, Tymchak W, Noga M, et al. Longterm treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation. 2003;108:2066–2069.

    Article  CAS  PubMed  Google Scholar 

  41. Ghofrani HA, Schermuly RT, Rose F, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2003;167:1139–1141.

    Article  PubMed  Google Scholar 

  42. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol. 2004;43:1149–1153.

    Article  CAS  PubMed  Google Scholar 

  43. Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J. 2006;151:851.

    Article  PubMed  Google Scholar 

  44. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. 2007;34:2417–2422.

    PubMed  Google Scholar 

  45. Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292–1297.

    Article  PubMed  Google Scholar 

  46. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24:1007–1010.

    Article  CAS  PubMed  Google Scholar 

  47. Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol. 2003;42:158–164.

    Article  CAS  PubMed  Google Scholar 

  48. Mukhopadhyay S, Sharma M, Ramakrishnan S, et al. Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study. Circulation. 2006;114:1807–1810.

    Article  CAS  PubMed  Google Scholar 

  49. Aizawa K, Hanaoka T, Kasai H, et al. Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension. Hypertens Res. 2006;29:123–128.

    Article  PubMed  Google Scholar 

  50. Montani D, Achouh L, Dorfmuller P, et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore). 2008;87:220–233.

    Article  Google Scholar 

  51. Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J. 2009;33:189–200.

    Article  CAS  PubMed  Google Scholar 

  52. Barreto AC, Franchi SM, Castro CR, Lopes AA. Oneyear follow-up of the effects of sildenafil on pulmonary arterial hypertension and veno-occlusive disease. Braz J Med Biol Res. 2005;38:185–195.

    Article  CAS  PubMed  Google Scholar 

  53. Creagh-Brown BC, Nicholson AG, Showkathali R, Gibbs JS, Howard LS. Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil. Thorax. 2008;63:933–934.

    Article  CAS  PubMed  Google Scholar 

  54. Montani D, Jais X, Price LC, et al. Cautious use of epoprostenol therapy is a safe bridge to lung transplantation in pulmonary veno-occlusive disease. Eur Respir J. 2009. DOI: 10.1183/09031936.00017809.

  55. Montani D, Jaïs X, Dorfmüller P, Simonneau G, Sitbon O, Humbert M. Goal-oriented therapy in pulmonary veno-occlusive disease: a word of caution. Eur Respir J. 2009. DOI: 10.1183/09031936.00102609.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Olivier Sitbon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Montani, D., Chaumais, MC., Savale, L. et al. Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension. Adv Therapy 26, 813–825 (2009). https://doi.org/10.1007/s12325-009-0064-z

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-009-0064-z

Keywords

Navigation