PDE5 inhibitors in non-urological conditions

Current Pharmaceutical Design

Volumn 15, Issue 30, 2009, Pages 3521-3539

  Vlachopoulos, C ^a   Terentes Printzios, D ^a   Ioakeimidis, N ^a   Rokkas, K ^a   Stefanadis, C ^a  

^a HIPPOKRATION HOSPITAL   (Greece)

Author keywords

Phosphodiesterase type 5 inhibitors; Sildenafil; Tadalafil; Vardenafil

Indexed keywords

BOSENTAN; CARDIOVASCULAR AGENT; ILOPROST; NITRATE; NITRIC OXIDE; PF 00489791; PHOSPHODIESTERASE V; PHOSPHODIESTERASE V INHIBITOR; PLACEBO; PROSTACYCLIN; SILDENAFIL; TADALAFIL; UNCLASSIFIED DRUG; UNIPROST; VARDENAFIL;

ALLERGIC ASTHMA; ALZHEIMER DISEASE; ANUS FISSURE; ARTERY INTIMA PROLIFERATION; ASTHMA; BRAIN TUMOR; CARDIOVASCULAR EFFECT; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; COLON DISEASE; CORONARY ARTERY DISEASE; CYSTIC FIBROSIS; DRUG APPROVAL; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG INDUCED HEADACHE; DRUG POTENTIATION; DRUG SAFETY; DRUG SELECTIVITY; DYSPEPSIA; DYSTHYMIA; EISENMENGER COMPLEX; ENDOTHELIAL DYSFUNCTION; ESOPHAGUS MOTILITY; ESOPHAGUS SPASM; EXERCISE; GENE EXPRESSION; HEART FAILURE; HEART MUSCLE ISCHEMIA; HEART PROTECTION; HEART TRANSPLANTATION; HUMAN; HYPERTENSION; ISCHEMIA COLON ANASTOMOSIS; ISCHEMIC COLON ANASTOMISIS; LONG TERM CARE; LUNG TRANSPLANTATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PHARMACOLOGICAL BLOCKING; PHYSICAL CAPACITY; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RAYNAUD PHENOMENON; REPERFUSION INJURY; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; SICKLE CELL ANEMIA; SKIN ULCER; SLEEP APNEA SYNDROME; STOMACH ULCER; STROKE; TREATMENT DURATION; TREATMENT INDICATION; TREATMENT RESPONSE; VASODILATATION;

ALZHEIMER DISEASE; ANIMALS; CARDIOVASCULAR DISEASES; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 5; ENDOCRINE SYSTEM DISEASES; EYE DISEASES; GASTROINTESTINAL DISEASES; HEMATOLOGIC DISEASES; HUMANS; LUNG DISEASES; NEOPLASMS; NERVOUS SYSTEM DISEASES; ORGAN TRANSPLANTATION; PHOSPHODIESTERASE INHIBITORS; SKIN DISEASES; STROKE;

EID: 70449367100     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161209789206980     Document Type: Review

References (235)

1. Lin CS, Lin G, Xin ZC, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 2006; 12: 3439-3457
2. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effect 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: 3C-12C. (Pubitemid 29122752)
3. Zhu B, Zhang L, Alexeyev M, Alvarez DF, Strada SJ, Stevens T. Type 5 phosphodiesterase expression is a critical determinant of the endothelial cell angiogenic phenotype. Am J Physiol Lung Cell Mol Physiol 2009; 296: L220-8.
4. Galiè 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. (Pubitemid 41653106)
5. Wilkins MR, Wharton J, Grimminger F, Ghofrani HA. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension. Eur Respir J 2008; 32: 198-209.
6. Kirsch M, Kemp-Harper B, Weissmann N, Grimminger F, Schmidt HH. Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling. FASEB J 2008; 22: 30-40.
7. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424-428. (Pubitemid 32678272)
8. Zhao L, Mason NA, Strange JW, Walker H, Wilkins MR. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic peptide activity. Circulation 2003; 107: 234-237. (Pubitemid 36135217)
9. Haynes J Jr, Kithas PA, Taylor AE, Strada SJ. Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity. Am J Physiol 1991; 261: H487-H492.
10. Cohen AH, Hanson K, Morris K, Fouty B, McMurty IF, Clarke W, et al. Inhibition of cyclic 3′-5′-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J Clin Invest 1996; 97: 172-179. (Pubitemid 26022592)
11. Sebkhi A, Strange JW, Phillips SC, Wharton J, Wilkins MR. Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 2003; 107: 3230-3235. (Pubitemid 36793096)
12. Schermuly RT, Kreisselmeier KP, Ghofrani HA, Yilmaz H, Butrous G, Ermert L, et al. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004; 169: 39-45. (Pubitemid 38233887)
13. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001; 29: 1000-1005 (Pubitemid 32424353)
14. Kleinsasser A, Loeckinger A, Hoerman C, Puehringer F, Mutz N, Bartsch G, et al. Sildenafil modulates hemodynamics and pulmonary gas exchange. Am J Resp Crit Care Med 2001; 163: 339-443. (Pubitemid 32158509)
15. Hemnes AR, Zaiman A, Champion HC. PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 2008; 294: L24-33.
16. Rossi R, Nuzzo A, Lattanzi A, Coppi F, Modena MG. Sildenafil improves endothelial function in patients with pulmonary hypertension. Pulm Pharmacol Ther 2008; 21: 172-177
17. Tsai BM, Turrentine MW, Sheridan BC, Wang M, Fiore AC, Brown JW, et al. Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg 2006; 81: 272-8.
18. Itoh T, Nagaya N, Fujii T, Iwase T, Nakanishi N, Hamada K, et al. A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med 2004; 169: 34-38.
19. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136: 515-522. (Pubitemid 34252285)
20. 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; 20: 2398-2403. (Pubitemid 34556392)
21. Lepore JJ, Maroo A, Pereira NL, Ginns LC, Dec GW, Zapol WM, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002; 90: 677-680. (Pubitemid 35264557)
22. Wilkens H, Guth A, König J, Forestier N, Cremers B, Hennen B, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001; 104: 1218-1222. (Pubitemid 32848108)
23. Ghofrani HA, Voswinckel R, Reichenberger F, Olschewski H, Haredza P, Karadaş B, 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: 488-496 (Pubitemid 39303954)
24. 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. (Pubitemid 38452588)
25. Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med 2005; 171: 1292-1297. (Pubitemid 40740738)
26. Michelakis ED, Tymchak W, Noga M, Webster L, Wu XC, Lien D, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003; 108: 2066-2069 (Pubitemid 37337580)
27. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007; 116: 1555-1562 (Pubitemid 47511419)
28. 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: 238-248. (Pubitemid 47196559)
29. Tay EL, Geok-Mui MK, Poh-Hoon MC, Yip J. Sustained benefit of tadalafil in patients with pulmonary arterial hypertension with prior response to sildenafil: A case series of 12 patients. Int J Cardiol 2008; 125: 416-417.
30. Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil Therapy for Pulmonary Arterial Hypertension. Circulation 2009; 119: 2894-2903
31. Aizawa K, Hanaoka T, Kasai H, Kogashi K, Kumazaki S, Koyama J, et al. Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension. Hypertens Res 2006; 29: 123-128
32. Giacomini M, Borotto E, Bosotti L, Denkewitz T, Reali-Forster C, Carlucci P, et al. Vardenafil and weaning from inhaled nitric oxide: effect on pulmonary hypertension in ARDS. Anaesth Intens Care 2007; 35: 91-93 (Pubitemid 46344292)
33. 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. (Pubitemid 39642293)
34. Mathai SC, Girgis RE, Fisher MR, Champion HC, Housten-Harris T, Zaiman A, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007; 29: 469-475. (Pubitemid 46372092)
35. Faruqi S, Fathi H, Morice AH. Combination of sitaxentan and tadalafil for idiopathic pulmonary arterial hypertension following relapse on bosentan. Int J Cardiol 2009; [Epub ahead of print].
36. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, 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 (Pubitemid 36760778)
37. Voswinckel R, Reichenberger F, Enke B, Kreckel A, Krick S, Gall H et al. Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Pulm Pharmacol Ther 2008; 21: 824-832
38. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, 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.
39. Bendayan D, Shitrit D, Kramer MR. Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study. Respirology 2008; 13: 916-918
40. Stehlik J, Movsesian MA. Combined use of PDE5 inhibitors and nitrates in the treatment of pulmonary arterial hypertension in patients with heart failure. J Cardiovasc Failure 2009; 15: 31-34
41. Schumacher YO, Zdebik A, Huonker M, Kreisel W. Sildenafil in HIV-related pulmonary hypertension. AIDS 2001; 15: 1747-1748.
42. Carlsen J, Kjeldsen K, Gerstoft J. Sildenafil as a successful treatment of otherwise fatal HIV-related pulmonary hypertension. AIDS 2002; 16: 1568-1569 (Pubitemid 34804229)
43. Ghofrani H, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360: 895-900. (Pubitemid 35283832)
44. Derchi G, Forni GL, Formisano F, Cappellini MD, Galanello R, D'Ascola G, et al. Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica 2005; 90: 452-458 (Pubitemid 40592887)
45. Klodell CT Jr, Morey TE, Lobato EB, Aranda JM Jr, Staples ED, Schofield RS, et al. Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices.Ann Thorac Surg 2007; 83(1): 68-71; discussion 71.
46. Lee JE, Hillier SC, Knoderer CA. Use of sildenafil to facilitate weaning from inhaled nitric oxide in children with pulmonary hypertension following surgery for congenital heart disease. J Intens Care Med 2008; 23: 329-334
47. Karatza AA, Buch A,Magee AG. Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol 2005; 200: 267-273 (Pubitemid 40502205)
48. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117: 1077-1083 (Pubitemid 46071498)
49. Ghofrani HA, Schermuly RT, Rose F, Wiedemann R, Kohstall MG, Kreckel A, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003; 167: 1139-1141. (Pubitemid 36459662)
50. Reichenberger F, Voswinckel R, Enke B, Rutsch M, El Fechtali E, Schmehl T, et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J 2007; 30: 922-927. (Pubitemid 351194796)
51. Suntharalingam J, Treacy CM, Doughty NJ, Goldsmith K, Soon E, Toshner MR, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest 2008; 134: 229-236
52. Reichenberger F, Voswinckel R, Steveling E, Enke B, Kreckel A, Olschewski H, et al. Sildenafil treatment for portopulmonary hypertension. Eur Respir J 2006; 28: 563-567
53. Hemnes AR, Robbins IM. Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation. Liver Transpl 2009; 15: 15-19
54. Higenbottam T. Pulmonary hypertension and chronic obstructive pulmonary disease: a case for treatment. Proc Am Thorac Soc 2005; 2: 12-19. (Pubitemid 40562957)
55. Alp S, Skrygan M, Schmidt WE, Bastian A. Sildenafil improves hemodynamic parameters in COPD - an investigation of six patients. Pulm Pharmacol Ther 2006; 19: 386-390. (Pubitemid 44234115)
56. Holverda S, Rietema H, Bogaard HJ, Westerhof N, Postmus PE, Boonstra A, et al. Acute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD. Pulm Pharmacol Ther 2008; 21: 558-564 (Pubitemid 351625938)
57. Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med 2004; 141: 169-177. (Pubitemid 39030866)
58. Aldashev AA, Kojonazarov BK, Amatov TA, Sooronbaev TM, Mirrakhimov MM, Morrell NW, et al. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax 2005; 60: 683-687. (Pubitemid 41129068)
59. Richalet JP, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005; 171: 275-281.
60. Hsu AR, Barnholt KE, Grundmann NK, Lin JH, McCallum SW, Friedlander AL. Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia. J Appl Physiol 2006; 100: 2031-2040.
61. Perimenis P. Sildenafil for the treatment of altitude-induced hypoxaemia. Expert Opin Pharmacother 2005; 6: 835-837
62. Chiu YJ, Reid IA. Effect of sildenafil on renin secretion in human subjects. Exp Biol Med 2002; 227: 620-625
63. Vlachopoulos C, Ioakeimidis N, Rokkas K, Stefanadis C. Cardiovascular effects of phosphodiesterase type 5 inhibitors. J Sex Med 2009; 6: 658-674
64. Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase type 5 inhibition in hypertension. Hypertension 2006; 48: 622-627 (Pubitemid 44843865)
65. Attinà TM, Malatino LS, Maxwell SR, Padfield PL, Webb DJ. Phosphodiesterase type 5 inhibition reverses impaired forearm exercise-induced vasodilatation in hypertensive patients. J Hypertens 2008; 26: 501-507
66. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: Methodological issues and clinical applications. Eur Heart J 2006; 27: 2588-2605 (Pubitemid 44627304)
67. Agabiti-Rosei E, Mancia G, O'Rourke MF, Roman MJ, Safar ME, Smulyan H, et al. Central blood pressure measurements and antihypertensive therapy: a consensus document. Hypertension 2007; 50: 154-160 (Pubitemid 46986036)
68. Vlachopoulos C, Hirata K, O'Rourke MF. Effect of sildenafil on arterial stiffness and wave reflection. Vasc Med 2003; 8: 243-248. (Pubitemid 38585138)
69. Mahmud A, Hennessy M, Feely J. Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men. J Hum Hypertens 2001; 15: 707-713. (Pubitemid 32975870)
70. Guimaraes GV, d'Avila VM, Pires P, Bacal F, Stolf N, Bocchi E. Acute effects of a single dose of phosphodiesterase type 5 inhibitor (sildenafil) on systemic arterial blood pressure during exercise and 24-hour ambulatory blood pressure monitoring in heart transplant recipients. Transplant Proc 2007; 39: 3142-3149
71. Patterson D, McInnes GT, Webster J, Mitchell MM, Macdonald TM. Influence of a single dose of 20 mg tadalafil, a phosphodiesterase 5 inhibitor, on ambulatory blood pressure in subjects with hypertension. Br J Clin Pharmacol 2006; 62: 280-287 (Pubitemid 44215527)
72. Wolk R, Smith WB, Neutel JM, Rubino J, Xuan D, Mancuso J, Gilbert J, Pressler ML, et al. Blood pressure lowering effects of a new long-acting inhibitor of phosphodiesterase 5 in patients with mild to moderate hypertension. Hypertension 2009; 53: 1091-1097
73. Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, et al. cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res 2005; 96: 100-109. (Pubitemid 40095759)
74. Chen Y, Traverse JH, Hou M, Li Y, Du R, Bache RJ. Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure. Am J Physiol Heart Circ Physiol 2003; 284: H1513-H1520. (Pubitemid 36460761)
75. Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA, et al. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation 2007; 115: 2159-2167 (Pubitemid 46659068)
76. Forfia PR, Lee M, Tunin RS, Mahmud M, Champion HC, Kass DA. Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart. J Am Coll Cardiol 2007; 49: 1079-1088. (Pubitemid 46349496)
77. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, et al. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol 2009; 53: 207-215
78. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, et al. Pressure-overload magnitude-dependence of the antihypertrophic efficacy of PDE5A inhibition. J Mol Cell Cardiol 2009; 46: 560-567
79. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005; 11: 214-222 (Pubitemid 40321358)
80. Borlaug BA, Melenovsky V, Marhin T, Fitzgerald P, Kass DA. Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans. Circulation 2005; 112: 2642-2649 (Pubitemid 41532601)
81. Salloum FN, Abbate A, Das A, Houser JE, Mudrick CA, Qureshi IZ, et al. Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol 2008; 294: H1398-H1406.
82. Kukreja RC. Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. Br J Pharmacol 2007; 150: 538-540 (Pubitemid 46355557)
83. Schäfer S, Ellinghaus P, Janssen W, Kramer F, Lustig K, Milting H, et al. Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling. Cardiovasc Res 2009; 82: 4-6
84. Andersen A, Nielsen JM, Peters CD, Schou UK, Sloth E, Nielsen-Kudsk JE. Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart. Eur J Heart Fail 2008; 10: 1158-1165
85. Kuhn M. Cardiac anti-remodelling effects of phosphodiesterase type 5 inhibitors: afterload-(in)dependent? Cardiovasc Res 2009; 82: 4-6.
86. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol 2000; 36: 845-851 (Pubitemid 30681608)
87. Hirata K, Adji A, Vlachopoulos C, O'Rourke MF. Effect of sildenafil on cardiac performance in patients with heart failure. Am J Cardiol 2005; 96: 1436-1440 (Pubitemid 41566628)
88. Hryniewicz K, Dimayuga C, Hudaihed A, Androne AS, Zheng H, Jankowski K. Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure. Clin Sci 2005; 108: 331-338 (Pubitemid 40516996)
89. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007; 50: 2136-2144 (Pubitemid 350117342)
90. Guazzi M, Casali M, Berti F, Rossoni G, Colonna VD, Guazzi MD. Endothelium-mediated modulation of ergoreflex and improvement in exercise ventilation by acute sildenafil in heart failure patients. Clin Pharmacol Ther 2008; 83: 336-341
91. Bocchi EA, Guimaraes G, Mocelin A, Bacal F, Bellotti G, Ramires JF. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002; 106: 1097-1103. (Pubitemid 34970850)
92. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilator efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol 2004; 44: 2339-2348. (Pubitemid 39647608)
93. Vlachopoulos C, Aznaouridis K, Ioakeimidis N, Rokkas K, Vasiliadou C, Alexopoulos N, et al. Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. Eur Heart J 2006; 27: 2640-2648 (Pubitemid 44729862)
94. Vlachopoulos C, Rokkas K, Ioakeimidis N, Stefanadis C. Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: Common links. Eur Urol 2007; 52: 1590-1600 (Pubitemid 350052419)
95. Morano S, Mandosi E, Fallarino M, Gatti A, Tiberti C, Sensi M, et al. Antioxidant treatment associated with sildenafil reduces monocyte activation and markers of endothelial damage in patients with diabetic erectile dysfunction: A double-blind, placebo-controlled study. Eur Urol 2007; 52: 1768-1776 (Pubitemid 350052399)
96. Aversa A, Greco E, Bruzziches R, Pili M, Rosano G, Spera G. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: A pilot study. Int J Impot Res 2007; 19: 200-207 (Pubitemid 46340840)
97. Aversa A, Vitale C, Volterrani M, Fabbri A, Spera G, Fini M, et al. Chronic administration of sildenafil improves markers of endothelial function in men with type 2 diabetes. Diabet Med 2008; 25: 37-44.
98. Vlachopoulos C, Tsekoura D, Alexopoulos N, Panagiotakos D, Aznaouridis K, Stefanadis C. Type 5 Phosphodiesterase inhibition by sildenafil abrogates acute smoking-induced endothelial dysfunction. Am J Hypertens 2004; 17: 1040-1044. (Pubitemid 39469327)
99. Konstantinopoulos A, Giannitsas K, Athanasopoulos A, Spathas D, Perimenis P. The impact of daily sildenafil on levels of soluble molecular markers of endothelial function in plasma in patients with erectile dysfunction. Expert Opin Pharmacother 2009; 10: 155-160
100. Behr-Roussel D, Oudot A, Caisey S, Coz OL, Gorny D, Bernabi J, et al. Daily treatment with sildenafil reverses endothelial dysfunction and oxidative stress in an animal model of insulin resistance. Eur Urol 2008; 53: 1272-1281 (Pubitemid 351615453)
101. Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Vinanzi C, et al. Relationship between vascular damage degrees and endothelial progenitor cells in patients with erectile dysfunction: Effect of vardenafil administration and PDE5 expression in the bone marrow. Eur Urol 2007; 51: 1411-1417 (Pubitemid 46436289)
102. Bocchio M, Pelliccione F, Passaquale G, Mihalca R, Necozione S, Desideri G, et al. Inhibition of phosphodiesterase type 5 with tadalafil is associated to an improved activity of circulating angiogenic cells in men with cardiovascular risk factors and erectile dysfunction. Atherosclerosis 2008; 196: 313-319
103. Hirschberg K, Radovits T, Loganathan S, Entz L, Beller CJ, Gross ML, et al. Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy. J Thorac Cardiovasc Surg 2009; 137: 1508-1514
104. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem 2005; 280: 12944-12955 (Pubitemid 40491117)
105. Pérez NG, Piaggio MR, Ennis IL, Garciarena CD, Morales C, Escudero EM, et al. Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction. Hypertension 2007; 49: 1095-1103 (Pubitemid 351664333)
106. Ahmad N, Wang Y, Ali AK, Ashraf M. Long acting phosphodiesterase inhibitor, tadalafil induces sustained cardioprotection against lethal ischemic injury. Am J Physiol Heart Circ Physiol 2009; 297: H387-91.
107. Vidavalur R, Penumathsa SV, Zhan L, Thirunavukkarasu M, Maulik N. Sildenafil induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin, hemeoxygenase and vascular endothelial growth factor. Vascul Pharmacol 2006; 45: 91-95 (Pubitemid 44374410)
108. Senthilkumar A, Smith RD, Khitha J, Arora N, Veerareddy S, Langston W, et al. Sildenafil promotes ischemia-induced angiogenesis through a PKG-dependent pathway. Arterioscler Thromb Vasc Biol 2007; 27: 1947-54. [109] Traverse JH, Chen YJ, Du R, Bache RJ. Cyclic nucleotide phosphodiesterase type 5 activity limits blood flow to hypoperfused myocardium during exercise. Circulation 2000; 102: 2997-3002. (Pubitemid 47312303)
109. 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 (Pubitemid 30341530)
110. Halcox JP, Nour KR, Zalos G, Mincemoyer RA, Waclawiw M, Rivera CE, et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol 2002; 40: 1232-42.
111. Tawakol A, Aziz K, Migrino R, Watkowska J, Zusman R, Alpert NM, et al. Effects of sildenafil on myocardial blood flow in humans with ischemic heart disease. Coronary Artery Dis 2005; 16: 443-449
112. Weinsaft JW, Hickey K, Bokhari S, Shahzad A, Bedding A, Costigan TM, et al. Effects of tadalafil on myocardial blood flow in patients with coronary artery disease. Coronary Artery Dis 2006; 17: 493-499 (Pubitemid 44231676)
113. Kostis JB, Jackson G, Rosen R, Barrett-Connor E, Billups K, Burnett AL, et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 2005; 96: 313-321 (Pubitemid 40978596)
114. Mittleman MA, Maclure M, Lewis MA, Hall GC, Moore N, Giuliano F, et al. Cardiovascular outcomes among sildenafil users: Results of the International Men's Health Study. Int J Clin Pract 2008; 62: 367-373 (Pubitemid 351197426)
115. Gazzaruso C, Solerte SB, Pujia A, Coppola A, Vezzoli M, Salvucci F, et al. Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease: A potential protective role for statins and 5-phosphodiesterase inhibitors. J Am Coll Cardiol 2008; 51: 2040-2044 (Pubitemid 351689055)
116. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, et al. 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
117. Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA 2002; 287: 719-725 (Pubitemid 34250457)
118. Thadani U, Smith W, Nash S, Bittar N, Glasser S, Narayan P, et al. The effects of vardenafil, a potent and highly selective phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2002; 40: 2006-2012 (Pubitemid 35425369)
119. Patterson D, MacDonald TM, Effron MB. Tadalafil does not affect time to ischemia during exercise testing in patients with coronary artery disease. Circulation 2002; 106(Suppl II): II-330.
120. Fox KM, Thadani U, Ma PT, Nash SD, Keating Z, Czomiak MA, et al. Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J 2003; 24: 2206-2212 (Pubitemid 37522673)
121. Kugiyama K, Yasue H, Okumura K, Ogawa H, Fujimoto K, Nakao K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation 1996; 94: 266-271 (Pubitemid 26266108)
122. Fung E, Fiscus RR, Yim AP, Angelini GD, Arifi AA. The potential use of type-5 phosphodiesterase inhibitors in coronary artery bypass graft surgery. Chest 2005; 128: 3065-3067 (Pubitemid 41507668)
123. Schmidt U, Han RO, DiSalvo TG, Guerrero JL, Gold HK, Zapol WM, et al. Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition. J Am Coll Cardiol 2001; 37: 1981-1988 (Pubitemid 32499990)
124. Lewis GD, Witzke C, Colon-Hernandez P, Guerrero JL, Bloch KD, Semigran MJ. Sildenafil improves coronary artery patency in a canine model of platelet-mediated cyclic coronary occlusion after thrombolysis. J Am Coll Cardiol 2006; 47: 1471-1477
125. Celermajer DS, Cullen S, Deanfield J. Impairment of endothelium-dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation 1993; 87: 440-446 (Pubitemid 23040913)
126. Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 2008; 117: 3020-3030
127. 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.e1-5
128. Chau EM, Fan KY, Chow WH. Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol 2007; 120: 301-305 (Pubitemid 47069563)
129. Garg N, Sharma MK, Sinha N. Role of oral sildenafil in severe pulmonary arterial hypertension: clinical efficacy and dose response relationship. Int J Cardiol 2007; 120: 306-313 (Pubitemid 47069567)
130. Lim ZS, Salmon AP, Vettukattil JJ, Veldtman GR. Sildenafil therapy for pulmonary arterial hypertension associated with atrial septal defects. Int J Cardiol 2007; 118: 178-182 (Pubitemid 46604774)
131. Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, Picchio FM. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J 2008; 29: 1681-1687 (Pubitemid 351957545)
132. Mukhopadhyay S, Sharma M, Ramakrishnan S, Yusuf J, Gupta MD, Bhamri N, et al. Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study. Circulation 2006; 114: 1807-1810 (Pubitemid 44673355)
133. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, openlabel, pilot study. Circulation 2005; 111: 3274-3280 (Pubitemid 40875000)
134. Caglayan E, Huntgeburth M, Karasch T, Weihrauch J, Hunzelmann N, Krieg T, et al. Phosphodiesterase type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med 2006; 166: 231-233 (Pubitemid 43144949)
135. Fries R, Shariat K, von Wilmowsky H, Böhm M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation 2005; 112: 2980-2985. (Pubitemid 41612301)
136. Gore J, Silver R. Oral sildenafil for the treatment of Raynaud's phenomenon and digital ulcers secondary to systemic sclerosis. Ann Rheum Dis 2005; 64: 1387. (Pubitemid 41206274)
137. Rosato E, Letizia C, Proietti M, Aversa A, Menghi G, Rossi C, et al. Plasma adrenomedullin and endothelin-1 levels are reduced and Raynaud's phenomenon improved by daily Tadalafil administration in male patients with systemic sclerosis. J Biol Regul Homeost Agents 2009; 23: 23-29
138. Dias-Junior CA, Vieira TF, Moreno H Jr, Evora PR, Tanus-Santos JE. Sildenafil selectively inhibits acute pulmonary embolism-induced pulmonary hypertension. Pulm Pharmacol Ther 2005; 18: 181-186 (Pubitemid 40222113)
139. Dias-Junior CA, Cau SB, Oliveira AM, Castro MM, Montenegro MF, Gerlach RF, et al. Nitrite or sildenafil, but not BAY 41-2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress. Thromb Res 2009; 124: 349-355
140. Krebs J, Ferguson SJ, Nuss K, Leskosek B, Hoerstrup SP, Goss BG, et al. Sildenafil prevents cardiovascular changes after bone marrow fat embolization in sheep. Anesthesiology 2007; 107: 75-81. (Pubitemid 46987822)
141. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 2002; 33: 2675-2680. (Pubitemid 35266440)
142. Zhang R, Wang L, Zhang L, Chen J, Zhu Z, Zhang Z, et al. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 2003; 92: 308-313. (Pubitemid 36258553)
143. Zhang L, Zhang RL, Wang Y, Zhang C, Zhang ZG, Meng H, et al. Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 2005; 36: 847-852. (Pubitemid 40490636)
144. Zhang RL, Zhang Z, Zhang L, Wang Y, Zhang C, Chopp M. Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res 2006; 83: 1213-1219. (Pubitemid 43668004)
145. Ding G, Jiang Q, Li L, Zhang L, Zhang ZG, Ledbetter KA, et al. Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab 2008; 28: 1440-1448
146. Zhang L, Zhang Z, Zhang RL, Cui Y, LaPointe M, Silver B, et al. Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 2006; 1118: 192-198. (Pubitemid 44633866)
147. Phillips BG, Kato M, Pesek CA, Winnicki M, Narkiewicz K, Davison D, et al. Sympathetic activation by sildenafil. Circulation 2000; 102: 3068-3073.
148. Puzzo D, Sapienza S, Arancio O, Palmeri A. Role of phosphodiesterase 5 in synaptic plasticity and memory. Neuropsychiatr Dis Treat 2008; 4: 371-387. (Pubitemid 351711932)
149. Menetti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS: targets for drug development. Nat Rev 2006; 5: 660-670. (Pubitemid 44151604)
150. Royl G, Balkaya M, Lehmann S, Lehnardt S, Stohlmann K, Lindauer U, et al. Effects of the PDE5-inhibitor vardenafil in a mouse stroke model. Brain Res 2009; 1265: 148-157
151. Kruse C, Thomsen LL, Jacobsen TB, Olesen JJ. The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow velocity but nevertheless induces headache in healthy subjects. Cereb Blood Flow Metab 2002; 22: 1124-1131.
152. Arnavz A, Aurich A, Weissenborn K, Hatmann U, Emmrich HM, Schneider U. Effect of sildenafil (Viagra) on cerebral blood flow velocity: a pilot study. Psychiatry Res 2003; 122: 207-209. (Pubitemid 36412196)
153. Rosengarten B. Sildenafil improves dynamic vascular function in the brain: studies in patients with pulmonary hypertension. Cerebrovasc Dis 2005; 21: 194-200.
154. Diomedi M, Sallustio F, Rizzato B, Ferrante F, Leone G, Spera E, et al. Sildenafil increases cerebrovascular reactivity: a transcranial Doppler study. Neurology 2005; 65: 919-921. (Pubitemid 41362141)
155. Nagdyman N, Fleck T, Bitterling B, Ewert P, Khalid HA, Stiller B, et al. Influence of intravenous sildenafil on cerebral oxygenation measured by near infrared spectroscopy in infants after cardiac surgery. Pediatr Res 2006; 59: 462-465. (Pubitemid 43740089)
156. Prickaerts J, Van Staveren WC, Sik A, Markerink-van Ittersum M, Niewohner U, van der Staay FJ, et al. Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience 2002; 113: 351-361. (Pubitemid 34786180)
157. Rutten K, Vente JD, Sik A, Ittersum MM, Prickaerts J, Blokland A. The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices. Behav Brain Res 2005; 164: 11-16. (Pubitemid 41253727)
158. Baratti CM, Boccia MM. Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice. Prog Neurobiol 2002; 68: 209-245.
159. Singh N, Parle M. Sildenafil improves acquisition and retention of memory in mice. Indian J Physiol Pharmacol 2003; 47: 318-24.
160. Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V. Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 2005; 41: 299Y306.
161. Ko IG, Shin MS, Kim BK, Kim SE, Sung YH, Kim TS, et al. Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. Pharmacol Biochem Behav 2009; 91: 629-635
162. Prickaerts J, Sik A, van Staveren WCG, Koopmans G, Steinbusch HWM, Van der Stay FJ, et al. Phosphodiesterase type 5 inhibition improves early memory consolidation of object information. Neurochem Int 2004; 45: 915-928. (Pubitemid 39108064)
163. Rutten K, Van Donkelaar EL, Ferrington L, Blokland A, Bollen E, Steinbusch HW, et al. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology 2009; 34: 1914-1925
164. Devan BD, Bowker JL, Duffy KB, Bharati IS, Jiminez M, Sierra- Mercado Jr D, et al. Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition. Psychopharmacology 2006; 183: 439-445.
165. Schultheiss D, Mueller SV, Nager W, Stief CG, Schlotte N, Jonas U, et al. Central effects of sildenafil (Viagra) on auditory selective attention and verbal recognition memory in humans: a study with event related brain potentials. World J Urol 2001; 19: 46-50. (Pubitemid 33777032)
166. Grass H, Klotz T, Fathian-Sabet B, Berghaus G, Engelmann U, Kaferstein H. Sildenafil (Viagra): is there an influence on psychological performance? Int Urol Nephrol 2001; 32: 409-412.
167. Brink CB, Clapton JD, Eagar BE, Harvey BH. Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies. J Neural Transm 2008; 115: 117-125
168. Orr G, Seidman SN, Weiser M, Gershon AA, Dubrov Y, Klein DF. An open-label pilot study to evaluate the efficacy of sildenafil citrate in middle-aged men with late-onset dysthymia. J Nerv Ment Dis 2008; 196: 496-500.
169. Asomoza-Espinosa R, Alonso-López R, Mixcoatl-Zecuatl T, Aguirre-Bañuelos P, Torres-López JE, Granados-Soto V. Sildenafil increases diclofenac antinociception in the formalin test. Eur J Pharmacol 2001; 418: 195-200. (Pubitemid 32441579)
170. Jain NK, Patil CS, Singh A, Kulkarni SK. Sildenafil induced peripheral analgesia and activation of the nitric oxide - cyclic GMP pathway. Brain Res 2001; 909: 170-178 (Pubitemid 32710130)
171. Patil CS, Singh VP, Singh S, Kulkarni SK. Modulatory effect of the PDE-5 inhibitor sildenafil in diabetic neuropathy. Pharmacology 2004; 72: 190-195 (Pubitemid 39370248)
172. Jain NK, Patil CS, Singh A, Kulkarni SK. Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine. Pharmacology 2003; 67: 150-156 (Pubitemid 36184460)
173. Eherer AJ, Schwetz I, Hammer HF, Petnehazy T, Scheidl SJ, Weber K, et al. Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders. Gut 2002; 50: 758-764 (Pubitemid 34539035)
174. Lee JI, Park H, Kim JH, Lee SI, Conklin JL. The effect of sildenafil on oesophageal motor function in healthy subjects and patients with nutcracker oesophagus. Neurogastroenterol Motil 2003; 15: 617-623 (Pubitemid 38030639)
175. Kim HS, Conklin JL, Park H. The effect of sildenafil on segmental oesophageal motility and gastro-oesophageal reflux. Aliment Pharmacol Ther 2006; 24: 1029-1036 (Pubitemid 44386527)
176. Fox M, Sweis R, Wong T, Anggiansah A. Sildenafil relieves symptoms and normalizes motility in patients with oesophageal spasm: A report of two cases. Neurogastroenterol Motil 2007; 19: 798-803. (Pubitemid 47460263)
177. Agrawal A, Tutuian R, Hila A, Castell DO. Successful use of phosphodiesterase type 5 inhibitors to control symptomatic esophageal hypercontractility: a case report. Dig Dis Sci 2005; 50: 2059-2062 (Pubitemid 41504089)
178. Watkins CC, Sawa A, Jaffrey S, Blackshaw S, Barrow RK, Snyder SH, et al. Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy. J Clin Invest 2000; 106: 373-84. Erratum in: J Clin Invest 2000; 106: 803. (Pubitemid 30655637)
179. Sarnelli G, Sifrim D, Janssens J, Tack J. Influence of sildenafil on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2004; 287: G988-92. (Pubitemid 38297110)
180. Sawatzky DA, Megson IL, Rossi AG. Sildenafil offers protection against NSAID-induced gastric injury. Br J Pharmacol 2005; 146: 477-478
181. Duffin R, Shaw CA, Rossi AG. Sildenafil reduces alcohol-induced gastric damage: just say "NO". Br J Pharmacol 2008; 153: 623-624
182. Jones OM, Brading AF, McC Mortensen NJ. Phosphodiesterase inhibitors cause relaxation of the internal anal sphincter in vitro. Dis Colon Rectum 2002; 45: 530-536. (Pubitemid 34407732)
183. Ballester C, Sarriá B, García-Granero E, Morcillo EJ, Lledó S, Cortijo J. Relaxation of the isolated human internal anal sphincter by sildenafil. Br J Surg 2007; 94: 894-902. (Pubitemid 47051216)
184. Torrabadella L, Salgado G, Burns RW, Berman IR. Manometric study of topical sildenafil (Viagra) in patients with chronic anal fissure: Sildenafil reduces anal resting tone. Dis Colon Rectum 2004; 47: 733-738 (Pubitemid 38585779)
185. Irkorucu O, Ucan BH, Cakmak GK, Emre AU, Tascilar O, Ofluoglu E, et al. Does sildenafil reverse the adverse effects of ischemia on ischemic colon anastomosis: yes, 'no'. Int J Surg 2009; 7: 39-43.
186. Ayten R, Cetinkaya Z, Girgin M, Ozercan I, Ustundag B, Aygen E. The effects of intraperitoneal sildenafil administration on healing of left colonic anastomoses and intra-abdominal adhesion formation in the presence of intra-abdominal infection. Dis Colon Rectum 2008; 51: 1837-1841
187. Uzun H, Konukoglu D, Nuri MK, Ersoy EY, Ozçevik S, Yavuz N. The effects of sildenafil citrate on ischemic colonic anastomotic healing in rats: its relationship between nitric oxide and oxidative stress. World J Surg 2008; 32: 2107-2113
188. Harris A, Kagemann L, Ehrlich R, Ehrlich Y, López CR, Purvin VA. The effect of sildenafil on ocular blood flow. Br J Ophthalmol 2008; 92: 469-473
189. Koksal M, Ozdemir H, Kargi S, Yesilli C, Tomac S, Mahmutyazicioglu K, et al. The effects of sildenafil on ocular blood flow. Acta Ophthalmol Scand 2005; 83: 355-359. (Pubitemid 40872511)
190. Foresta C, Caretta N, Zuccarello D, Poletti A, Biagioli A, Caretti L, et al. Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects. Eye 2008; 22: 144-149.
191. Metelitsina TI, Grunwald JE, DuPont JC, Ying GS. Effect of Viagra on the foveolar choroidal circulation of AMD patients. Exp Eye Res 2005; 81: 159-164.
192. Laties AM. Vision disorders and phosphodiesterase type 5 inhibitors: a review of the evidence to date. Drug Saf 2009; 32: 1-18.
193. Sarfati M, Mateo V, Baudet S, Rubio M, Fernandez C, Davi F, et al. Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells. Blood 2003;101:265-269 (Pubitemid 36025917)
194. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006; 203: 2691-2702 (Pubitemid 44833345)
195. Treon SP, Tournilhac O, Branagan AR, Hunter Z, Xu L, Hatjiharissi E, et al. Clinical responses to sildenafil in Waldenstrom's macroglobulinemia. Clin Lymphoma 2004; 5: 205-207 (Pubitemid 40227715)
196. Black KL, Yin D, Ong JM, Hu J, Konda BM, Wang X, et al. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res 2008; 1230: 290-302.
197. Toward TJ, Smith N, Broadley KJ. Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Am J Respir Crit Care Med 2004; 169: 227-234 (Pubitemid 38114539)
198. Wang T, Liu Y, Chen L, Wang X, Hu XR, Feng YL, et al. Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur Respir J 2009; 33: 1122-1132
199. Al Qadi-Nassar B, Bichon-Laurent F, Portet K, Tramini P, Arnoux B, Michel A. Effects of L-arginine and phosphodiesterase-5 inhibitor, sildenafil, on inflammation and airway responsiveness of sensitized BP2 mice. Fundamen Clin Pharmacol 2007; 21: 611-620 (Pubitemid 350151247)
200. Clayton RA, Dick CA, Mackenzie A, Nagasawa M, Galbraith D, Hastings SF, et al. The effect of selective phosphodiesterase inhibitors, alone and in combination, on a murine model of allergic asthma. Respir Res 2004; 5: 4. (Pubitemid 41358091)
201. Perimenis P, Karkoulias K, Markou S, Gyftopoulos K, Athanasopoulos A, Barbalias G, et al. Erectile dysfunction in men with obstructive sleep apnea syndrome: a randomized study of the efficacy of sildenafil and continuous positive airway pressure. Int J Impot Res 2004; 16: 256-260 (Pubitemid 38858959)
202. Perimenis P, Karkoulias K, Konstantinopoulos A, Perimeni PP, Katsenis G, Athanasopoulos A, et al. Sildenafil versus continuous positive airway pressure for erectile dysfunction in men with obstructive sleep apnea: a comparative study of their efficacy and safety and the patient's satisfaction with treatment. Asian J Androl 2007; 9: 259-64.
203. Perimenis P, Konstantinopoulos A, Karkoulias K, Markou S, Perimeni P, Spyropoulos K. Sildenafil combined with continuous positive airway pressure for treatment of erectile dysfunction in men with obstructive sleep apnea. Int Urol Nephrol 2007; 39: 547-552
204. Roizenblatt S, Guilleminault C, Poyares D, Cintra F, Kauati A, Tufik S. A double-blind, placebo-controlled, crossover study of sildenafil in obstructive sleep apnea. Arch Intern Med 2006; 166: 1763-1767 [Erratum in: Arch Intern Med 2007; 167: 207]. (Pubitemid 44414466)
205. Perimenis P, Giannitsas K. Safety of sildenafil in the treatment of erectile dysfunction in patients with obstructive sleep apnoea. Expert Opin Drug Saf 2007; 6: 423-430 (Pubitemid 351308171)
206. McPherson MA, Pereira MMC, Lloyd-Mills C, Murray KJ, Dormer RL. A cyclic nucleotide PDE5 inhibitor corrects defective mucin secretion in submandibular cells containing antibody directed against the cystic fibrosis transmembrane conductance regulator protein. FEBS Lett 1999; 464: 48-52.
207. Cobb BR, Fan L, Kovacs TE, Sorscher EJ, Clancy JP. Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells. Am J Respir Cell Mol Biol 2003; 29: 410-418. (Pubitemid 37094001)
208. Carlile GW, Robert R, Zhang D, Teske KA, Luo Y, Hanrahan JW, et al. Correctors of protein trafficking defects identified by a novel high-throughput screening assay. ChemBioChem 2007; 8: 1012-1020. (Pubitemid 47189285)
209. Dormer RL, Harris CM, Clark Z, Pereira MMC, Doull IJM, Norez C, et al. Sildenafil (Viagra) corrects DF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis. Thorax 2005; 60: 55-59. (Pubitemid 40101019)
210. Poschet JF, Timmins GS, Taylor-Cousar JL, Ornatowski W, Fazio J, Perkett E, et al. Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. Am J Physiol 2007; 293: L712-L719. (Pubitemid 47358834)
211. Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, et al. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med 2008; 177: 506-515.
212. Gertner E. Treatment with sildenafil for the healing of refractory skin ulcerations in the antiphospholipid syndrome. Lupus 2003; 12: 133-135 (Pubitemid 36240847)
213. Colglazier CL, Sutej PG, O'Rourke KS. Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil. J Rheumatol 2005; 32: 2440-2442
214. Hart K, Baur D, Hodam J, Lesoon-Wood L, Parham M, Keith K, et al. Short- and long-term effects of sildenafil on skin flap survival in rats. Laryngoscope 2006; 116: 522-528 (Pubitemid 44318059)
215. Ulusoy MG, Uysal A, Koçer U, Karaaslan O, Cuzdan SS, Ayyildiz A, Ustün H, et al. Improved flap viability with site-specific delivery of sildenafil citrate using fibrin glue. Ann Plast Surg 2005; 55:292-296 (Pubitemid 41216089)
216. Tsai JW, Ayubi FS, Hart KL, Baur DA, Parham MA, Moon JK, et al. Evaluation of the effect of sildenafil and vascular endothelium growth factor combination treatment on skin flap survival in rats. Aesthetic Plast Surg 2008; 32: 624-631
217. Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR, et al. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol 2005; 130: 445-453 (Pubitemid 43899595)
218. Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 2007; 110: 2166-2172 (Pubitemid 47443936)
219. Little JA, Hauser KP, Martyr SE, Harris A, Maric I, Morris CR, et al. Hematologic, biochemical, and cardiopulmonary effects of Larginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy. Eur J Haematol 2009; 82: 315-321
220. Schäfer A, Fraccarollo D, Pförtsch S, Flierl U, Vogt C, Pfrang J, et al. Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus. Br J Pharmacol 2008; 153: 886-893 (Pubitemid 351328925)
221. Radovits T, Bömicke T, Kökény G, Arif R, Loganathan S, Kécsán K, et al. The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus. Br J Pharmacol 2009; 156: 909-919
222. Burnett AL, Strong TD, Trock BJ, Jin L, Bivalacqua TJ, Musicki B. Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J Urol 2009; 181: 245-251
223. Hill KD, Eckhauser AW, Marney A, Brown NJ. Phosphodiesterase 5 inhibition improves beta-cell function in metabolic syndrome. Diabetes Care 2009; 32: 857-859
224. Hackett G. PDE5 inhibitors in diabetic peripheral neuropathy. Int J Clin Pract 2006; 60: 1123-1126 (Pubitemid 44226753)
225. Grover-Páez F, Villegas Rivera G, Guillén Ortíz R. Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with type 2 diabetes. Diabetes Res Clin Pract 2007; 78: 136-140 (Pubitemid 47351245)
226. Korom S, Hillinger S, Cardell M, Zhai W, Tan Q, Dutly A, et al. Sildenafil extends survival and graft function in a large animal lung transplantation model. Eur J Cardiothorac Surg 2006; 29: 288-293 (Pubitemid 43207565)
227. Pizanis N, Milekhin V, Tsagakis K, Aleksic I, Kamler M, Jakob H. PDE-5 inhibitor donor intravenous preconditioning is superior to supplementation in standard preservation solution in experimental lung transplantation. Eur J Cardiothorac Surg 2007; 32: 42-47 (Pubitemid 46874982)
228. Pizanis N, Heckmann J, Wendt D, Tsagakis K, Jakob H, Kamler M. Improvement of pulmonary microcirculation after lung transplantation using phosphodiesterase-5 inhibitor modified preservation solution. Eur J Cardiothorac Surg 2009; 35: 801-6..
229. Weiss ES, Champion HC, Williams JA, Baumgartner WA, Shah AS. Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model. J Thorac Cardiovasc Surg 2009; 137: 1249-1257
230. Jabbour A, Keogh A, Hayward C, Macdonald P. Chronic sildenafil lowers transpulmonary gradient and improves cardiac output allowing successful heart transplantation. Eur J Heart Fail 2007; 9: 674-677 (Pubitemid 46702813)
231. De Santo LS, Mastroianni C, Romano G, Amarelli C, Marra C, Maiello C, et al. Role of sildenafil in acute posttransplant right ventricular dysfunction: successful experience in 13 consecutive patients. Transplant Proc 2008; 40: 2015-2018
232. Schofield RS, Schuler BT, Edwards DG, Aranda JM Jr, Hill JA, Nichols WW. Amplitude and timing of central aortic pressure wave reflections in heart transplant recipients. Am J Hypertens 2002; 15: 809-815
233. Aversa A, Caprio M, Rosano GM, Spera G. Endothelial effects of drugs designed to treat erectile dysfunction. Curr Pharm Des 2008; 14(35): 3768-3778
234. Srivani P, Usharani D, Jemmis ED, Sastry GN. Subtype selectivity in phosphodiesterase 4 (PDE4): a bottleneck in rational drug design. Curr Pharm Des 2008; 14(36): 3854-3872
235. Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, Stefanadis C. The triad: erectile dysfunction - endothelial dysfunction - cardiovascular disease. Curr Pharm Des 2008; 14(35): 3700-3714