PDE5 inhibitors beyond erectile dysfunction

International Journal of Impotence Research

Volumn 19, Issue 6, 2007, Pages 533-543

  Sandner, P ^a   Hutter J ^a   Tinel, H ^a   Ziegelbauer, K ^a   Bischoff, E ^a  

^a Bayer HealthCare   (Germany)

Author keywords

Benign prostate syndrome; Heart failure; Lower urinary tract symptoms; Peyronie's disease; Premature ejaculation; Raynaud's disease

Indexed keywords

AVANAFIL; BOTULINUM TOXIN; CYCLIC GMP; ENDOTHELIAL NITRIC OXIDE SYNTHASE; INDUCIBLE NITRIC OXIDE SYNTHASE; LOCAL ANESTHETIC AGENT; MITOGEN ACTIVATED PROTEIN KINASE 1; MUSCARINIC RECEPTOR BLOCKING AGENT; NITRIC OXIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHODIESTERASE V; PHOSPHODIESTERASE V INHIBITOR; PROTEIN KINASE B; RAMIPRIL; RESINIFERATOXIN; SEROTONIN UPTAKE INHIBITOR; SILDENAFIL; SLX 2101; TADALAFIL; TRANSCRIPTION FACTOR NFAT; TRICYCLIC ANTIDEPRESSANT AGENT; UDENAFIL; UNCLASSIFIED DRUG; VARDENAFIL; ZAPRINAST;

BRAIN ISCHEMIA; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DRUG EFFICACY; DRUG INDICATION; DRUG SAFETY; DRUG TOLERABILITY; DYSPEPSIA; ENDOTHELIAL DYSFUNCTION; ERECTILE DYSFUNCTION; FEMALE SEXUAL DYSFUNCTION; HEADACHE; HUMAN; HYPOACTIVE SEXUAL DESIRE DISORDER; LOWER URINARY TRACT SYMPTOM; NONHUMAN; OVERACTIVE BLADDER; PEYRONIE DISEASE; PREMATURE EJACULATION; PRIAPISM; PRIORITY JOURNAL; PROSTATE HYPERTROPHY; PULMONARY HYPERTENSION; RAYNAUD PHENOMENON; REVIEW; SEXUAL AROUSAL DISORDER; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; STROKE; TREATMENT RESPONSE; URINE INCONTINENCE;

ANIMALS; CARDIOVASCULAR DISEASES; CENTRAL NERVOUS SYSTEM DISEASES; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 5; ERECTILE DYSFUNCTION; HUMANS; MALE; PHOSPHODIESTERASE INHIBITORS; UROLOGIC DISEASES;

EID: 35848941746     PISSN: 09559930     EISSN: 14765489     Source Type: Journal    
DOI: 10.1038/sj.ijir.3901577     Document Type: Review

References (127)

1. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology pathophysiology and pharmacology. Pharmacol Rev 1991; 43: 109-142.
2. Conti M. Phosphodiesterases and cyclic nucleotide signalling in endocrine cells. Mol Endocrinol 2000; 14: 1317-1327.
3. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S et al. Guanylyl cyclases an signaling by cGMP. Pharmacol Rev 2000; 52: 375-414.
4. Corbin JD, Francis SH, Webb DJ. Phosphodiesterase-type 5 as target in treatment of erectile dysfunction. Urology 2002; 60: 4-11.
5. Salem EA, Kendirici M, Hellstrom WJ. Udenafil, a long-acting PDE5 ihhibitor for erectile dysfunction. Curr Opin Investig Drugs 2006; 7: 661-669.
6. Kaufmann JM, Aurora CO, Dietrich JW. Safety and efficacy of avanafil, a new phosphodiesterase type5 (PDE5) inhibitor for treating erectile dysfunction. J Urol 2006; 175(4) Suppl: 299.
7. Prince W, Campbell AS, Tong W, Sweetnam P, Willett M, Roesch BG et al. SLX-2101, a new long-acting PDE5 inhibitor: preliminary safety, tolerability, PK and endothelial function effects in healthy subjects. J Urol 2006; 175(4) Suppl: 299.
8. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003; 93: 280-291.
9. Uckert S, Kuthe A, Jonas U, Stief CG. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol 2001; 166: 2484-2490.
10. Truss MC, Uckert S, Stief CG, Kuczyk MA, Jonas U. Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle: I. Identification and characterisation. Urol Res 1996; 24: 123-128.
11. Stacey P, Sulten S, Dapling A, Phillips SC. Molecular cloning and expression of human cGMP-binding cGMP-specific phosphodiesterase (PDE5). Biochem Biophys Res Commun 1998; 247: 249-254.
12. Loughney K, Hill TR, Florio VA, Uher L, Rosmann GJ, Wolda SL et al. Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase. Gene 1998; 216: 139-147.
13. Kotera J, Fujishige K, Omori K. Immunohistochemical localization of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in rat tissues. J Histochem Cytochem 2000; 48: 685-693.
14. Lin CS, Lin G, Xin ZC, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Design 2006; 12: 3439-3457.
15. Kukreja RC, Salloum F, Das A, Ockaili R, Yin C, Bremer YA et al. Pharmacological preconditioning with sildenafil: basic mechanisms and clinical implications. Vascul Pharmacol 2005; 42: 219-232.
16. 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.
17. Tinel H, Stelte-Ludwig B, Huetter J, Sandner P. Preclinical evidences for the use of PDE5 inhbitors for treating benign prostate hyperplasia and lower urinary tract symptoms. BJU Int 2006; 98: 1259-1263.
18. Ferrini MG, Kovanecz I, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease. BJU Int 2006; 97: 625-633.
19. 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.
20. 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.
21. 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.
22. Galie 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: 2148-2157.
23. 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 ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol 2004; 44: 2339-2348.
24. 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.
25. Katz SD. Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. Congest Heart Fail 2003; 9: 9-15.
26. 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.
27. Hryniewicz K, Dimayuga C, Hudaihed A, Androne AS, Zheng H, Jankowski K et al. Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure. Clin Sci (London) 2005; 108: 331-338.
28. Chen Y, Traverse JH, Hou M, Li Y, Du R, Bache RJ. Effect of PDE-5 inhibition on coronary hemodynamics in pacing-induced heart failure. Am J Physiol 2003; 284: H1513-H1520.
29. Stoyneva Z, Lyapina M, Tzvetkov D, Vodenicharov E. Current pathophysiological views on vibration-induced Raynaud's phenomenon. Cardiovasc Res 2003; 57: 615-624.
30. Freedman RR, Girgis R, Mayes MD. Acute effect of nitric oxide on Raynaud's phenomenon in scleroderma. Lancet 1999; 354: 739.
31. Rosenkranz S, Diet F, Karasch T, Weihrauch J, Wassermann K, Erdmann E. Sildenafil improved pulmonary hypertension and peripheral blood flow in a patient with scleroderma-associated lung fibrosis and the Raynaud phenomenon. Ann Intern Med 2003; 139: 871-873.
32. Caglayan E, Huntgeburth M, Karasch T, Weihrauch J, Hunzelmann N, Krieg T et al. The phosphodiesterase type 5 inhibitor vardenafil increases peripheral blood flow in patients with Raynauld syndrome. Circulation 2004; 110: 142.
33. 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.
34. Menetti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS: targets for drug development. Nat Rev 2006; 5: 660-670.
35. Blockland A, Schreiber R, Prickaerts J. Improving memory: a role for phosphodiesterases. Curr Pharm Des 2006; 12: 2511-2523.
36. 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.
37. Loughney K, Hill TR, Florio VA, Uher L, Rosman GJ, Wolda SL et al. Isolation and characterisation of cDNA encoding PDE-5A, a human cGMP binding, cGMP specific 3′5′-cyclic nucleotide phosphodiesterase. Gene 1998; 216: 139-147.
38. Van Staveren WC, Steinbusch HW, Markerink-Van Ittersum M, Repaske DR, Goy MF, Kotera J et al. mRNA expression patterns of the cGMP hydrolyzing phosphodiesterases types 2, 5, 9 during development of rat brain. J Comp Neurol 2003; 467: 566-580.
39. Kruse LS, Sandholt NTH, Gammeltoft S, Olesen J, Kruuse C. Phosphodiesterase 3′ and 5 cyclic nucleotide gated ion channel expression in rat trigemino vascular system. Neurosci Lett 2006; 404: 202-207.
40. Hoheisel U, Unger T, Mense S. The possible role of the NO-cGMP pathway in nociception: different spinal and supraspinal action of enzyme blockers on rat dorsal horn neurones. Pain 2005; 117: 358-367.
41. Milman HA, Arnold SB. Neurologic, psychological, and aggresive disturbances with sildenafil. Ann Pharmocother 2002; 36: 1129-1134.
42. 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.
43. Bernabeu R, Schmitz P, Faillace MP, Izquierdo I, Medina JH. Hippocampal cGMP and cAMP are differently involved in memory processing of inhibitory avoidance learning. Neuroreport 1996; 7: 585-588.
44. Baratti CM, Boccia MM. Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice. Prog Neurobiol 2002; 68: 209-245.
45. 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.
46. 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.
47. Patil CS, Singh VP, Kulkarni SK. Modulatory effect of sildenafil in diabetes and electroconvulsive shock induced cognitive dysfunction in rats. Pharmacol Rep 2006; 58: 373-380.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. Wang L, Gang ZZ, Lan ZR, Chopp M. Activation of the PI3-K/Akt pathway mediates cGMP enhanced neurogenesis in the adult progenitor cells derived from the subventricular zone. J Cereb Blood Flow Metab 2005; 25: 1150-1158.
54. 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.
55. Amavz 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.
56. Rosengarten B. Sildenafil improves dynamic vascular function in the brain: studies in patients with pulmonary hypertension. Cerebrovasc Dis 2005; 21: 194-200.
57. 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.
58. 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: 612-617.
59. Uckert S, Oelke M, Waldkirch E, Stief CG, Albrecht K, Troger HD et al. Cyclic adenosine monophosphate and cyclic guanosine monophosphate- phosphodiesterase isoenzymes in human vagina: relation to nitric oxide synthase isoforms and vasoactive intestinal polypeptide-containing nerves. Urology 2005; 65: 604-610.
60. Oelke M, Hedlund P, Albrecht K, Ellinghaus P, Stief CG, Jonas U et al. Expression of cAMP and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study. Urology 2006; 67: 1111-1116.
61. Uckert S, Ehlers V, Nuser V, Oelke M, Kauffels W, Scheller F et al. In vitro functional responses of isolated human vaginal tissue to selective phosphodiesterase inhibitors. World J Urol 2005; 23: 398-404.
62. Tinel H, Huetter J, Sander P. PDE-5 inhibition relaxes isolated rat vaginal strips and rat clitoral corpus cavernosum. J Sex Med 2006; 3(Suppl 5): 399.
63. Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled study. BJOG 2001; 108: 623-628.
64. Basson R, McInnes R, Smith MD, Hodgson G, Koppiker N. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J Womens Health Gend Based Med 2002; 11: 367-377.
65. Basson R, Brotto LA. Sexual psychophysiology and effects of sildenafil citrate in oestrogenised women with acquired genital arousal disorder and impaired orgasm: a randomized controlled trial. BJOG 2003; 110: 1014-1024.
66. Berman JR, Berman LA, Toler SM, Gill J, Haughie S, Sildenafil Study Group. Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J Urol 2003; 170: 2333-2338.
67. Enzlin P, Mathieu C, Van den Bruel A, Bosteels J, Vanderschueren D, Demyttenaere K. Sexual dysfunction in women with type 1 diabetes: a controlled study. Diabetes Care 2002; 25: 672-677.
68. Caruso S, Rugolo S, Agnello C, Intelisano G, Di Mari L, Cianci A. Sildenafil improves sexual functioning in premenopausal women with type 1 diabetes who are affected by sexual arousal disorder: a double-blind, crossover, placebo-controlled pilot study. Fertil Steril 2006; 85: 1496-1501.
69. Laan E, EveraerdW, van der Velde J, Geer JH. Determinants of subjective experience of sexual arousal in women: feedback from genital arousal and erotic stimulus content. Psychophysiology 1995; 32: 444-451.
70. Cain VS, Johannes CB, Avis NE, Mohr B, Schocken M, Skurnick J et al. Sexual functioning and practices in a multiethnic study of midlife women: baseline results from SWAN. J Sex Res 2003; 40: 266-276.
71. Basson R. Clinical practice. Sexual desire and arousal disorders in women. N Engl J Med 2006; 354: 1497-1506.
72. Althof SE, Rosen RC, DeRogatis L, Corty E, Quirk F, Symonds T. Outcome measurement in female sexual dysfunction clinical trials: review and recommendations. J Sex Marital Ther 2005; 31: 153-166.
73. Abrams P. New words for old: lower urinary tract symptoms for prostatism. BMJ 1994; 308: 929-930.
74. Holtgrewe HL. Current trend in management of men with lower urinary tract symptoms and benign prostate hyperplasia. Urology 1998; 51: 1-7.
75. Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Euro Urol 2006; 49: 651-659.
76. Guess HA. Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 1995; 22: 247-261.
77. Carbone Jr DJ, Hodges S. Medical therapy for benign prostatic hyperplasia: sexual dysfunction and impact on quality of life. Int J Impot Res 2003; 15: 299-306.
78. Kuciel R, Ostroski W. Phosphodiesterase from human prostate gland. Bull Soc Chim Biol 1970; 52: 1051-1060.
79. Uckert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P. Immunohistochemical distribution of cAMP-and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 2006; 49: 740-745.
80. Drescher P, Eckert RE, Madsen PO. Smooth muscle contractility in prostatic hyperplasia: role of cyclic adenosine monophosphate. Prostate 1994; 25: 76-80.
81. Filippi S, Morelli A, Sandner P, Fibbi B, Mancina R, Marini M et al. Characterization and functional role of an androgen-dependent PDE-5 activity in bladder. Endocrinology 2007; 148: 1019-1029.
82. McVary KT, Monning W, Camps JL, Joung JM, Tseng LJ, Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tracts symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 2007; 177: 1071-1077.
83. Kaplan SA, Gonzalez RR, Ogiste J, Te AE. Combination of an alpha blocker, alfuzosin SR and a PDE-5 inhibitor, sildenafil citrate is superior to monotherapy in treating lower urinary tract symptoms (LUTS) and sexual dysfunction. J Urol 2006; 175: S528.
84. Roehrborn CG, McVary KT, Kaminetsky JC, Auerbach SM, Wachs B, Young JM et al. The efficacy and safety of tadalafil administered once a day for lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). J Urol 2006; 175: S527.
85. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167-178.
86. Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. How widespread are the symptoms of the overactive bladder and how are they managed? A population based prevalence study. BJU Int 2001; 87: 760-766.
87. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 2004; 84: 935-986.
88. Sahai A, Khan MS, Arya M, John J, Singh R, Patel HRH. The overactive bladder: review of current pharmacotherapy in adults. Part2: treatment options in cases refractory to anticholinergics. Expert Opin Pharmacother 2006; 7: 529-538.
89. Patterson JM, Chapple CR. Botulinum toxin in urinary incontinence. Curr Opin Urol 2006; 16: 255-260.
90. Sahai A, Khan MS, Arya M, John J, Singh R, Patel HRH. The overactive bladder: review of current pharmacotherapy in adults. Part 1: Pathophysiology and anticholinergics therapy. Expert Opin Pharmacother 2006; 7: 509-527.
91. Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Euro Urol 2005; 48: 5-26.
92. Truss MC, Uckert S, Stief CG, Kuczyk MA, Jonas U. Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle: II. Effect of various PDE-inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. Urol Res 1996; 24: 123-128.
93. Qiu Y, Kraft P, Craig EC, Liu X, Haynes-Johnson D. Identification and functional study of phosphodiesterases in rat urinary bladder. Urol Res 2001; 29: 388-392.
94. Qiu Y, Kraft P, Craig EC, Liu X, Haynes-Johnson D. Cyclic nucleotide phosphodiesterases in rabbit detrusor smooth muscle. Urology 2002; 59: 145-149.
95. Uckert ST, Seemann C, Stief CG, Lietz B, Neuhaus L, Bischoff E et al. Funktionelle in vitro-effekte cAMP/cGMP moduliernder Pharmaka am humanen Detrusormuskel. J Urol Urogynäkol 2002; 9: 7-14.
96. Gillespie JI, Drake MJ. The actions of sodium nitropursside and the phosphodiesterase inhibitor dipyridamole on phasic activity in the isolated guinea-pig bladder. BJU Int 2004; 93: 851-858.
97. Gillespie JI, Markerink-van Ittersum M, De Vente J. Endogenous nitric oxide/cGMP signaling in the guinea pig bladder: evidence for distinct population of sub-urothelial interstitial cells. Cell Tissue Res 2006; 325: 325-332.
98. Truss MC, Stief CG, Uckert S, Becker AJ, Schultheiss D, Machtens S et al. Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder. World J Urol 2000; 18: 439-443.
99. Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU 2004; 94: 817-820.
100. Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 2006; 296: 2319-2328.
101. Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med 2006; 3: 662-667.
102. Aschka C, Himmel W, Ittner E, Kochen MM. Sexual problems of male patients in family practice. J Fam Pract 2001; 50: 773-778.
103. Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF et al. AUA guideline on the pharmacologic management of premature ejaculation. J Urol 2004; 172: 290-294.
104. Althof SE. Prevalence, characteristics and implication of premature ejaculation/rapid ejaculation. J Urol 2006; 175: 842-848.
105. Hellstrom WJ. Current and future pharmacotherapies of premature ejaculation. J Sex Med 2006; 3(Suppl 4): 332-341.
106. Piediferro G, Colpi EM, Castiglioni F, Scroppo FI. Premature ejaculation 3. Therapy. Arch Ital Uro Andro 2004; 76: 192-198.
107. Schultz KD, Schultz K, Schultz G. Sodium nitroprusside and other smooth muscle relaxants increase cGMP levels in rat ductus deferens. Nature 1977; 265: 750-751.
108. Bialy M, Beck J, Abramczyk P, Treszebski A, Przybylski J. Sexual behaviour in male rats after nitric oxide synthase inhibition. Physiol Behav 1996; 60: 139-143.
109. Heuer O, Ueckert S, Machtens SA, Stief CG, Tsikas D, Froehlich JC et al. Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro. Urology 2002; 59: 958-962.
110. Machtens S, Ueckert S, Stief CG, Tsiskas D, Froehlich JC, Jonas U. Effects of various nitric oxide-donating drugs on adrenergic tension of human seminal vesicles in vitro. Urology 2003; 61: 479-483.
111. Mancina R, Filippi S, Marini M, Morelli A, Vignozzi L, Salonia A et al. Expression and functional activity of phosphodiesterase type 5 in human and rabbit vas deferens. Mol Hum Reprod 2005; 11: 107-115.
112. Kriegsfeld LJ, Demas GE, Huang PL, Burnett AL, Nelson RJ. Ejaculatory abnormalities in mice lacking the gene for endothelia nitric oxide synthase (eNOS-/-). Physiol Behav 1999; 67: 561-566.
113. McMahon CG, McMahon CN, Leow LJ, Winestock CG. Efficacy of type5 phosphodiesterase inhibitors in the drug treatment of premature ejaculation: a systematic review. BJU 2006; 98: 259-272.
114. Wang WF, Minhas S, Ralph DJ. Phosphodiesterase 5 inhibitors in the treatment of premature ejaculation. Intl J Androl 2006; 29: 503-509.
115. Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, Tekdogan U. Comparison of efficacy of sildenafil-only, sildenafil plus topical EMLA cream, and topical EMLA-cream-only in treatment of premature ejaculation. Urology 2006; 67: 388-391.
116. Sommer F, Klotz T, Mathers MJ. Treatment of premature ejaculation: a comparative vardenafil and SSRI crossover study. J Urol 2005; 173(Suppl.): 202.
117. Mattos RM, Lucon AM. Tadalafil and slow-release fluoxetine in premature ejaculation - a prospective study. J Urol 2005; 173(Suppl.): 239.
118. McMahon CG, Stuckey BGA, Andersen M, Purvis K, Koppiker N, Haughie S et al. Efficacy of sildenafil citrate (Viagra) in men with premature ejaculation. J Sex Med 2005; 2: 368-375.
119. Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L et al. Peyronie's disease. J Sex Med 2004; 1: 110-115.
120. Mulhall JP, Creech SD, Boorjian SA, Ghaly S, Kim ED, Moty A et al. Subjective and objective analysis of the prevalence of Peyronie's disease in a population of men presenting for prostate cancer screening. J Urol 2004; 171: 2350-2353.
121. Ferrini MG, Vernet D, Magee TR, Shahed A, Qian A, Rajfer J et al. Antifibrotic role of inducible nitric oxide synthase. Nitric Oxide 2002; 6: 283-294.
122. Valente EG, Vernet D, Ferrini MG, Qian A, Rajfer J, Gonzalez-Cadavid NF. L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie's fibrotic plaque and related fibroblast cultures. Nitric Oxide 2003; 9: 229-244.
123. Ferrini MG, Davila HH, Kovanecz I, Sanchez SP, Gonzalez-Cadavid NF, Rajfer J. Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology 2006; 68: 429-435.
124. Burnett AL. Pathophysiology of priapism: dysregulatory erection physiology thesis. J Urol 2003; 170: 26-34.
125. Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L et al. Priapism. J Sex Med 2004; 1: 116-120.
126. Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Longterm oral phosphodiesterase5 inhibitor therapy alleviates recurrent priapism. J Urol 2006; 67: 1043-1048.
127. Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Feasibility of the use of phosphodiesterase type 5 inhibitors in a pharmacologic prevention program for recurrent priapism. J Sex Med 2006; 3: 1077-1084.