ABSTRACT

Pulmonary hypertension (PH) is a pathology of pulmonary circulation. Its prototype, idiopathic pulmonary hypertension (IPAH), is model of investigations directed to early diagnosis and treatment. The vascular pulmonary endothelium has a predominant role in the disease, it different changes modify the pulmonary vascular tone, specifically decreased in production or response to nitric oxide.
Treatment of pulmonary hypertension, is directed to decrease pulmonary pressure and vascular pulmonary resistance, increase survival and modify quality of life. Patients with response in the vascular pulmonary reactivity test during right side cardiac catheterism, long-term treatment with calcium channel antagonist drugs are effective in 30% of the cases. In the clinical spectrum, the high percent of patients without response during the test begins research of other candidates. Different drugs with vascular properties, like nitric oxide, prostaciclin analogs (ej. Epoprostenol, iloprost), and endothelin 1 inhibitors (bosentan) showed important results. Recently begins the phosphodiesterase 5 inhibitors evaluation because of their effects on pulmonary vascular response.
Sildenafil, vardenafil and tadalafil are effective in the treatment of erectile dysfunction; they have pulmonary vasodilatatory effects by increasing nitric oxide levels and inhibition of endothelial phosphodiesterase 5. Long-term treatment with sildenafil in IPAH or PH associated to collagen vascular disease, or chronic thromboembolic disease showed favorable results in quality of life and survival. The effectiveness of the phosphodiesterase 5 inhibitors in different types of PH is under investigation.

KEYWORDS

Sildenafil, tadalafil, vardenafil, pulmonary hypertension.

REFERENCES

1. Rubin JL. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126: 7S-10S.

2. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352: 719-25.

3. Peacock AJ. Primary pulmonary hypertension. Thorax 1999; 54: 1107-18.

4. Tuder R, Cool C, Gerasi M. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Resp Crit Care Med 1999; 159: 1925-32.

5. Morales-Blanhir J, Santos S, de Jover L, Sala E, Parè C, Roca J, Rodriguez-Roisin R, Barberà J. Clinical value of vasodilator test with inhaled nitric oxide for predicting long-term response to oral vasodilators in pulmonary hypertension. Resp Medicine 2004; 98: 225-34.

6. 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.

7. Campos CR, Rosas RMJ, Morales-Blanhir JE. Iloprost en hipertensión pulmonar: Renacimiento de un viejo conocido. Neumol Cir Torax 2006; 65: 132-45.

8. Rubin L, Badesch D, Barst RJ, Galiè N, Black C, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. For the bosentan randomized trial of endothelin antagonist therapy study group. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903.

9. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-57.

10. Saldanha MBS. Nossas diretrizes em hipertensão pulmonar. J Bras Pneumol 2005; 31: 20.

11. Ghofrani HA, Wiedemann R, Rose F,Olschewsky H, Schermuly RT, Weissmann N. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Int Med 2002; 136: 515-22.

12. Wilkens H, Guth A, König J, Forestier N, Cremers B, Hennen B. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001; 104: 1218-22.

13. García E, Brandao A. Sildenafil for patients with portopulmonary hypertension, candidates to hepatic transplant. Thematic poster session: pulmonary hypertension. European Respiratory Congress, Glasgow England 2004.

14. Michelakis E, Tymchak W, Lien D. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension. Circulation 2002; 105: 2398-2403.

15. Higenbottam TW, Laude EA. Endothelial dysfunction providing the basis for the treatment of pulmonary hypertension. Chest 1998; 114(Suppl): 72-6.

16. Horstman D, Frank D, Rich G. Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats. Anesth Analg 1998; 86: 74-9.

17. Cargill R, Kley D, Clark R, Lipworth B. Hypoxemia and release of endotelin-1. Thorax 1995; 50: 1308-14.

18. Peng W, Michael J, Hoidal J. ET-1 modulatesKCa-channel activity and arterial tension in normoxicand hypoxic human pulmonary vasculature. Am J Physiol 1998; 275: L729.

19. Holm P, Liska J, Franco-Cereceda A. The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo. Cardiovasc Res 1998; 37: 765-71.

20. 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: 214-20.

21. www.nobel.se/medicine/laureats/1998

22. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough. Hepatology 2002; 35: 478-91.

23. Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 1998; 114: 298S-312S.

24. Cooper CJ, Landzberg MJ, Anderson TJ. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation 1996; 93: 266-71.

25. Ricciardi MJ, Knigth BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension. A safe and effective agent for redicting response to nifedipine. J Am Coll Cardiol 1998; 32: 1068-73.

26. Krauski R, Warner J, Wang A. Inhaled nitric oxide selectively dilates pulmonary vascular in adult patient with pulmonary hypertension, irrespective of etiology. J Am Coll Cardiol 2000; 36: 2204-09.

27. Roger N, Barberà JA, Roca J, Rovira I, Gómez FP, Rodríguez-Roisin R. Nitric oxide inhalation during exercise in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 1997; 156: 800-6.

28. Cockrill BA, Kacmarek RM, Fifer MA, Bigatello LM, Ginns LC, Zapol WM, Semigran MJ. Comparison of the effects of nitric oxide, nitroprusside, and nifedipine on hemodynamics and right ventricular contractility in patients with chronic pulmonary hypertension. Chest 2001; 119:128-36.

29. Channick RN, Yung GL. Long-term use of inhaled nitric oxide for pulmonary hypertension. Resp Care 1999; 44: 212-9.

30. Koh E, Niimura J, Nakamura T. Long-term inhalation of nitric oxide for a patient with primary pulmonary hypertension. Jpn Circ L 1998; 62: 940-2.

31. Snell GI, Salamonsen RF, Bergin P. Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. Am J Resp Crit Care Med 1995; 151: 1263-6.

32. Jamieson SW. Pulmonary thromboendarterectomy. Herat 1998; 79: 118-20.

33. Kirklin JK, Naftel DC, Kirklin JW. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant 1988; 7: 331-6.

34. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75: 725-48.

35. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr. Use of sildenafil in patients with cardiovascular disease. Technology and Practice Executive Committee. Circulation. 1999; 99: 168-77.

36. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000; 84: E4.

37. Buck LM. Sildenafil for the treatment of pulmonary hypertension in children. Pediatric Pharm 2004; 10: 2-9.

38. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998; 338: 1397-404.

39. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999; 83(5A): 3C-12C.

40. Forrester JS, Douglas PS, Faxon DP, Fisher JD, Gibbons RJ, Halperin JL, Hutter AM, Hochman JS, Kaul S. Use of sildenafil in patients with cardiovascular disease. Circulation. 1999; 99: 168-177.

41. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, Block LH. Long term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003; 123: 1293-95.

42. Lodato RF. Viagra for impotence of pulmonary vasodilator therapy? Am J Resp Crit Care Med 2001; 163: 312.

43. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47-52.

44. Vobig MA, Klotz T, Staak M, Bartz-Schmidt KU, Engelmann U, Walter P. Retinal side-effects of sildenafil. Lancet 1999; 353: 375-78.

45. Park K, Moreland RB, Goldstein I, Atala A, Traish A. Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1998; 249: 612-7.

46. Cooper JD, Muirhead DC, Taylor JE, Baker PR. Development of an assay for the simultaneous determination of sildenafil and its metabolite (UK-103,320) using automated sequential trace enrichment of dialysates and high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1997; 701: 87-95.

47. Umrani DN, Goyal RK. Pharmacology of sildenafil citrate. Indian J Physiol Pharmacol 1999; 43: 160-4.

48. Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 1999; 83(5A): 35C-44C.

49. Hedelin H. A new agent against impotence. Contraindicated in reduced renal and hepatic function, in angina and with simultaneously used nitroglycerin preparations. Lakartidningen 1998; 95: 4558-60.

50. 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: 273-82.

51. Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83(5A): 21C-28C.

52. Zusman RM, Prisant LM, Brown MJ. Effect of sildenafil citrate on blood pressure heart rate in men with erectile dysfunction taking concomitant antihypertensive medications. J Hypertens 2000; 18: 1865-9.

53. Leuchte HH, Schwaiblmair M, Baumgartner RA, Neurohr CF, Kolbe T, Behr J. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest 2004; 125: 580-86.

54. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomized controlled trial. Lancet 2002; 360(9337): 895-900.

55. Mikhaila GW, Prasada SK, Lia W, Rogersa P, Chesterb AH, Baynea S, Stephensc D, Khanb M, Gibbsd JS, Evansa TW, Mitchella A, Yacoubb MH, Gatzoulisa MA. Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid term effects. Eur Heart J 2004; 25: 431-36.

56. Preston IR, Klinger JR, Houtches J, Nelson D, Farber HW, Hill NS. Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension. Respir Med 2005; 99: 1501-10.

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

58. Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadas B, Schermuly RT, Weissman N, Seeger W, Grimminger F. Differences in hemodynamic and oxygenation responses to three different phospodiesterase-5 inhibitors in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2004; 44: 1488-96.

59. Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005; 60: 107-12.

60. Makisalo H, Koivusalo A, Vakkuri A, Hockerstedt K. Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transpl 2004; 10: 945-50.

61. Chua R, Keogh A, Miyashita M. Novel use of sildenafil in the treatment of portopulmonary hypertension. J Heart Lung Transplant 2005; 24: 498-500.

62. Wang YW, Lin HC, Yang YY, Hou MC, Lee SD. Sildenafil decreased pulmonary arterial pressure but may have exacerbated portal hypertension in a patient with cirrhosis and portopulmonary hypertension. J Gastroenterol 2006; 41: 593-7.

63. Reichenberger F, Voswinckel R, Steveling E, Enke B, Kreckel A, Olschewski H, Grimminger F, Seeger W, Ghofrani HA. Sildenafil treatment for portopulmonary hypertension. Eur Respir J 2006; 28: 563-567.

64. Kataoka M, Satoh T, Manabe T, Anzai T, Yoshikawa T, Mitamura H, Ogawa S. Marked improvement with sildenafil in a patient with primary pulmonary hypertension unresponsive to epoprostenol. Int Med 2003; 43: 945-50.

65. Jiménez López-Guarch C, Escribano-Subias P, Tello de Meneses R, Delgado-Jiménez JF, Sadia-Pérez D, Velásquez-Martín MT, Gómez-Sánchez MA, Sáenz de la Calzada C. Efficacy of oral sildenafil as rescue therapy in patients with severe pulmonary arterial hypertension chronically treated with prostacyclin. Long-term results. Rev Esp Cardiol 2004; 57: 946-51.

66. Humbert M, Simonneau G. Sildenafil for pulmonary arterial hypertension: still waiting for evidence. Am J Respir Crit Care Med 2004; 169: 6-7.

67. Zhao L, Mason NA, Morrell NW. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424-28.

68. Givertz MM, Colucci WS, LeJemtel TH. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000; 101: 2922-2927.

69. Lepore JJ, MarooA, Bigatello LM, Dec GW, Zapol WM, Bloch KD, Semigran MJ. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension. Combined administration with inhaled nitric oxide Chest 2005; 127: 1647-53.

70. Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD, Staples ED, Beaver TM. Oral sildenafil reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 2005; 79: 194-7.

71. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomized trial in infants after cardiac surgery. Intensive Care Med 2003; 29: 1996-2003.

72. Roland F, Shariat K, von Wilmowsky H, Böhm M. Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy. Circulation 2005; 112: 2980-5.

73. Goldenberg MM. Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin Ther 1998; 20: 1033-48.

74. Prisant LM. Phosphodiesterase-5 inhibitors and their hemodynamic effects. Curr Hypertens Rep 2006; 8: 345-51.

75. Kapur V, Rodriguez J, Rastogi S, Rosanio S. The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. Int J Impot Res 2006; 10: 1038-45.

76. Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil. Am J Cardiol 2003; 92(9A): 37M-46M.

77. Affuso F, Palmieri EA, Di Conza P, Guardasole V, Fazio S. Tadalafil improves quality of life and exercise tolerance in idiopathic pulmonary arterial hypertension. Int J Cardiol 2006; 108: 429-31.

78. Maggiorini M, Brunner-La Rocca HP, Peth S, Fischler M, Bohm T, Bernheim A, Kiencke S, Bloch KE, Dehnert C, Naeije R, Lehmann T, Bartsch P, Mairbaurl H. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med 2006; 145: 497-506.

79. Pomara G, Morelli G, Pomara S, Taddei S, Ghiadoni L, Dinelli N, Travaglini F, Dicuio M, Mondaini N, Salvetti A, Selli C. Cardiovascular parameter changes in patients with erectile dysfunction using PDE-5 inhibitors: a study with sildenafil and vardenafil. J Androl 2004; 25: 625-29.

80. Aizawa K, Hanaoka T, Kasai H, Kogashi K, Kumazaki S, Koyama J, Tsutsui H, Yazaki Y, Watanabe N, Kinoshita O, Ikeda U. Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension. Hypertens Res 2006; 29: 123-28.

81. Rubin L. Pulmonary arterial hypertension. Proc Am Thorac Soc 2006; 3: 111-5.