The role of phosphodiesterases in bladder pathophysiology

Nature Reviews Urology

Volumn 10, Issue 7, 2013, Pages 414-424

  Rahnama'i, Mohammad S ^a   Ückert, Stefan ^b   Hohnen, Ramona ^c   Van Koeveringe, Gommert A ^a  

^a MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

^b HANNOVER MEDICAL SCHOOL   (Germany)

^c MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

4 (3 CHLOROPHENYL) 1,7 DIETHYLPYRIDO[2,3 D]PYRIMIDIN 2(1H) ONE; ALFUZOSIN; CYCLIC AMP; CYCLIC GMP; GISADENAFIL; IC 486051; PHOSPHODIESTERASE; PHOSPHODIESTERASE I; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; PHOSPHODIESTERASE V; PLACEBO; ROLIPRAM; SILDENAFIL; SOLIFENACIN; SPLEEN EXONUCLEASE; TADALAFIL; TAMSULOSIN; UDENAFIL; UNCLASSIFIED DRUG; VARDENAFIL; VINPOCETINE; ZAPRINAST;

BLADDER DISEASE; BLADDER FUNCTION; BLADDER NECK STENOSIS; DRUG EFFECT; DRUG EFFICACY; DRUG MEGADOSE; ENZYME INHIBITION; ERECTILE DYSFUNCTION; HEMORRHAGIC CYSTITIS; HUMAN; LOWER URINARY TRACT SYMPTOM; MICTURITION; MICTURITION DISORDER; MULTICENTER STUDY (TOPIC); MUSCLE RELAXATION; NONHUMAN; OVERACTIVE BLADDER; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SINGLE DRUG DOSE; URINARY FREQUENCY;

ANIMALS; ERECTILE DYSFUNCTION; FEMALE; HUMANS; LOWER URINARY TRACT SYMPTOMS; MALE; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; URINARY BLADDER; URINARY BLADDER DISEASES; URINARY BLADDER, OVERACTIVE;

EID: 84880278062     PISSN: 17594812     EISSN: 17594820     Source Type: Journal    
DOI: 10.1038/nrurol.2013.101     Document Type: Review

References (106)

1. Beavo, J. A. Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiol. Rev. 75, 725-748 (1995
2. Rybalkin, S. D., Yan, C., Bornfeldt, K. E. & Beavo, J. A. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ. Res. 93, 280-291 (2003 (Pubitemid 37048240)
3. Maurice, D. H. et al. Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol. Pharmacol. 64, 533-546 (2003 (Pubitemid 37048555)
4. Kamenetsky, M. et al. Molecular details of cAMP generation in mammalian cells: A tale of two systems. J. Mol. Biol. 362, 623-639 (2006 (Pubitemid 44332423)
5. Dessauer, C. W. Adenylyl cyclase - A-kinase anchoring protein complexes: The next dimension in cAMP signalling. Mol. Pharmacol. 76, 935-941 (2009
6. Lucas, K. A. et al. Guanylyl cyclases and signalling by cyclic GMP. Pharmacol. Rev. 52, 375-414 (2000
7. Moncada, S., Palmer, R. M. & Higgs, E. A. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109-142 (1991
8. Andersson, K. E. & Persson, K. Nitric oxide synthase and nitric oxide-mediated effects in lower urinary tract smooth muscles. World J. Urol. 12, 274-280 (1994
9. Andersson, K. E. & Persson, K. Nitric oxide synthase and the lower urinary tract: Possible implications for physiology and pathophysiology. Scand. J. Urol. Nephrol. Suppl. 175, 43-53 (1995
10. Carvajal, J. A., Germain, A. M., Huidobro-Toro, J. P. & Weiner, C. P. Molecular mechanism of cGMP-mediated smooth muscle relaxation. J. Cell. Physiol. 184, 409-420 (2000 (Pubitemid 30625505)
11. Uckert, S. et al. Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: Present and future. Eur. Urol. 50, 1194-1207 (2006 (Pubitemid 44692918)
12. Gillespie, J. I. Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated bladder. BJU Int. 93, 1325-1332 (2004 (Pubitemid 38823962)
13. Hanna-Mitchell, A. T. & Birder, L. A. New insights into the pharmacology of the bladder. Curr. Opin. Urol. 18, 347-352 (2008 (Pubitemid 351787150)
14. Kedia, G. T., Uckert, S., Jonas, U., Kuczyk, M. A. & Burchardt, M. The nitric oxide pathway in the human prostate: Clinical implications in men with lower urinary tract symptoms. World J. Urol. 26, 603-609 (2008
15. Andersson, K. E., Uckert, S., Stief, C. & Hedlund, P. Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS. Neurourol. Urodyn. 26, 928-933 (2007 (Pubitemid 47548230)
16. Uckert, S. & Kuczyk, M. A. Cyclic nucleotide metabolism including nitric oxide and phosphodiesterase-related targets in the lower urinary tract. Handb. Exp. Pharmacol. 2011, 527-542 (2011
17. Montorsi, F., Corbin, J. & Phillips, S. Review of phosphodiesterases in the urogenital system: New directions for therapeutic intervention. J. Sex. Med. 1, 322-336 (2004 (Pubitemid 40424643)
18. Alm, P., Larsson, B., Ekblad, E., Sundler, F. & Andersson, K. E. Immunohistochemical localization of peripheral nitric oxide synthase-containing nerves using antibodies raised against synthesized C-and N-terminal fragments of a cloned enzyme from rat brain. Acta Physiol. Scand. 148, 421-429 (1993 (Pubitemid 23234551)
19. Birder, L. A., Apodaca, G., De Groat, W. C. & Kanai, A. J. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am. J. Physiol. 275, F226-F229 (1998
20. Persson, K., Poljakovic, M., Johansson, K. & Larsson, B. Morphological and biochemical investigation of nitric oxide synthase and related enzymes in the rat and pig urothelium. J. Histochem. Cytochem. 47, 739-750 (1999
21. Fujiwara, M., Andersson, K. & Persson, K. Nitric oxide-induced cGMP accumulation in the mouse bladder is not related to smooth muscle relaxation. Eur. J. Pharmacol. 401, 241-250 (2000 (Pubitemid 30488203)
22. Persson, K. et al. Functional characteristics of urinary tract smooth muscles in mice lacking cGMP protein kinase type I. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1112-R1120 (2000
23. Kanai, A. et al. Mechanisms of action of botulinum neurotoxins, β3-adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011. Neurourol. Urodyn. 31, 300-308 (2012
24. Uckert, S. & Oelke, M. Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction. Br. J. Clin. Pharmacol. 72, 197-204 (2011
25. Essayan, D. M. Cyclic nucleotide phosphodiesterases. J. Allergy Clin. Immunol. 108, 671-680 (2001 (Pubitemid 33096193)
26. Essayan, D. M. Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem. Pharmacol. 57, 965-973 (1999 (Pubitemid 29168544)
27. Soderling, S. H., Bayuga, S. J. & Beavo, J. A. Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase. Proc. Natl Acad. Sci. USA 95, 8991-8996 (1998 (Pubitemid 28350602)
28. Soderling, S. H., Bayuga, S. J. & Beavo, J. A. Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J. Biol. Chem. 273, 15553-15558 (1998 (Pubitemid 28298167)
29. Conti, M. & Jin, S. L. The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 63, 1-38 (1999
30. Gupta, R., Kumar, G. & Kumar, R. S. An update on cyclic nucleotide phosphodiesterase (PDE) inhibitors: Phosphodiesterases and drug selectivity. Methods Find. Exp. Clin. Pharmacol. 27, 101-118 (2005
31. Filippi, S. et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 148, 1019-1029 (2007
32. Rahnama'i, M. S. et al. Distribution of phosphodiesterase type 5 (PDE5) in the lateral wall of the guinea pig urinary bladder. BJU Int. http://dx.doi.org/10.1111/bju.12031
33. Uckert, S. et al. Significance of phosphodiesterase isoenzymes in the control of human detrusor smooth muscle function. An immunohistochemical and functional study [German]. Urologe A 48, 764-769 (2009
34. Morley, D. J. et al. Distribution of phosphodiesterase I in normal human tissues. J. Histochem. Cytochem. 35, 75-82 (1987 (Pubitemid 17221600)
35. Nagasaki, S. et al. Phosphodiesterase type 9 (PDE9) in the human lower urinary tract: An immunohistochemical study. BJU Int. 109, 934-940 (2012
36. Uckert, S., Kuthe, A., Jonas, U. & Stief, C. G. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J. Urol. 166, 2484-2490 (2001 (Pubitemid 33065340)
37. Kuthe, A. et al. Gene expression of the phosphodiesterases 3A and 5A in human corpus cavernosum penis. Eur. Urol. 38, 108-114 (2000 (Pubitemid 30418026)
38. Qiu, Y., Kraft, P., Craig, E. C., Liu, X. & Haynes-Johnson, D. Cyclic nucleotide phosphodiesterases in rabbit detrusor smooth muscle. Urology 59, 145-149 (2002 (Pubitemid 34059337)
39. Xin, W., Soder, R. P., Cheng, Q., Rovner, E. S. & Petkov, G. V. Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle: Role for ryanodine receptor mediated BK channel activation. Am. J. Physiol. Cell Physiol. 303, C1079-C1089 (2012
40. Truss, M. C. et al. Effects of various phosphodiesterase-inhibitors, forskolin, and sodium nitroprusside on porcine detrusor smooth muscle tonic responses to muscarinergic stimulation and cyclic nucleotide levels in vitro. Neurourol. Urodyn. 15, 59-70 (1996
41. Truss, M. C., Uckert, S., Stief, C. G., Forssmann, W. G. & 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. 24, 129-134 (1996 (Pubitemid 26226248)
42. Fock, E. M., Lavrova, E. A., Bachteeva, V. T., Chernigovskaya, E. V. & Parnova, R. G. Nitric oxide inhibits arginine-vasotocin-induced increase of water osmotic permeability in frog urinary bladder. Pflugers Arch. 448, 197-203 (2004 (Pubitemid 38648180)
43. Oger, S. et al. Relaxation of phasic contractile activity of human detrusor strips by cyclic nucleotide phosphodiesterase type 4 inhibition. Eur. Urol. 51, 771-780 (2007
44. Nishiguchi, J. et al. Suppression of detrusor overactivity in rats with bladder outlet obstruction by a type 4 phosphodiesterase inhibitor. BJU Int. 99, 680-686 (2007 (Pubitemid 46238850)
45. Kitta, T., Tanaka, H., Mitsui, T., Moriya, K. & Nonomura, K. Type 4 phosphodiesterase inhibitor suppresses experimental bladder inflammation. BJU Int. 102, 1472-1476 (2008
46. Buyuknacar, H. S., Kumcu, E. K., Gocmen, C. & Onder, S. Effect of phosphodiesterase type 4 inhibitor rolipram on cyclophosphamide-induced cystitis in rats. Eur. J. Pharmacol. 586, 293-299 (2008
47. Longhurst, P. A., Briscoe, J. A., Rosenberg, D. J. & Leggett, R. E. The role of cyclic nucleotides in guinea-pig bladder contractility. Br. J. Pharmacol. 121, 1665-1672 (1997 (Pubitemid 27343394)
48. Werkstrom, V., Hedlund, P., Lee, T. & Andersson, K. E. Vardenafil-induced relaxation and cyclic nucleotide levels in normal and obstructed rat urinary bladder. BJU Int. 104, 1740-1745 (2009
49. Lee, J. G. et al. Relaxation effect of phosphodiesterase-5 inhibitor on the animal bladder and prostatic urethra: in vitro and in vivo study. Urol. Int. 84, 231-235 (2010
50. Behr-Roussel, D. et al. Vardenafil decreases bladder afferent nerve activity in unanaesthetized, decerebrate, spinal cord-injured rats. Eur. Urol. 59, 272-279 (2011
51. Chen, H. D., Ye, X. T., Weng, Z. L. & Li, C. D. Effects and mechanisms of phosphodiesterase type 5 inhibitors on rats with overactive bladder [Chinese]. Zhonghua Yi Xue Za Zhi 91, 2001-2005 (2011
52. Morelli, A. et al. Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J. Sex. Med. 7, 107-120 (2010
53. Matsumoto, S., Hanai, T. & Uemura, H. Chronic treatment with a PDE5 inhibitor increases contractile force of normal bladder in rats. Int. Urol. Nephrol. 42, 53-56 (2010
54. Morelli, A. et al. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signalling pathway in spontaneously hypertensive rats. J. Sex. Med. 6, 1594-1608 (2009
55. Caremel, R., Oger-Roussel, S., Behr-Roussel, D., Grise, P. & Giuliano, F. A. Nitric oxide/cyclic guanosine monophosphate signalling mediates an inhibitory action on sensory pathways of the micturition reflex in the rat. Eur. Urol. 58, 616-625 (2010
56. Minagawa, T., Aizawa, N., Igawa, Y. & Wyndaele, J. J. Inhibitory effects of phosphodiesterase 5 inhibitor, tadalafil, on mechanosensitive bladder afferent nerve activities of the rat, and on acrolein-induced hyperactivity of these nerves. BJU Int. 110 (Pt B), E259-E266 (2012
57. Yanai, Y. et al. Role of nitric oxide/cyclic GMP pathway in regulating spontaneous excitations in detrusor smooth muscle of the guinea-pig bladder. Neurourol. Urodyn. 27, 446-453 (2008 (Pubitemid 351991212)
58. Matsumoto, S., Hanai, T., Uemura, H. & Levin, R. M. Effects of chronic treatment with vardenafil, a phosphodiesterase 5 inhibitor, on female rat bladder in a partial bladder outlet obstruction model. BJU Int. 103, 987-990 (2009
59. Kang, K. K. et al. Effects of phosphodiesterase type 5 inhibitor on the contractility of prostate tissues and urethral pressure responses in a rat model of benign prostate hyperplasia. Int. J. Urol. 14, 946-951 (2007 (Pubitemid 47429170)
60. Beamon, C. R., Mazar, C., Salkini, M. W., Phull, H. S. & Comiter, C. V. The effect of sildenafil citrate on bladder outlet obstruction: A mouse model. BJU Int. 104, 252-256 (2009
61. Bittencourt, J. A. et al. Relaxant effects of sildenafil on the human isolated bladder neck. Urology 73, 427-430 (2009
62. Oger, S. et al. Signalling pathways involved in sildenafil-induced relaxation of human bladder dome smooth muscle. Br. J. Pharmacol. 160, 1135-1143 (2010
63. Kedia, G. T., Bodmann, F., Kuczyk, M. A. & Ückert, S. Stimulation of the cyclic AMP/cyclic GMP signalling enhances the relaxation exerted by phosphodiesterase (PDE) inhibitors of isolated human detrusor smooth muscle. Eur. Urol. Suppl. 11, e738 (2012
64. Truss, M. C. 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. 18, 439-443 (2000
65. Truss, M. S. et al. Phosphodiesterase 1 inhibition in the treatment of urinary urgency and urge incontinence - results of the vinpocetine multicentre trial. World J. Urol. 19, 344-350 (2001
66. Hatzimouratidis, K. Sildenafil in the treatment of erectile dysfunction: An overview of the clinical evidence. Clin. Interv. Aging 1, 403-414 (2006
67. Qaseem, A. et al. Hormonal testing and pharmacologic treatment of erectile dysfunction: A clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 151, 639-649 (2009
68. Sairam, K., Kulinskaya, E., McNicholas, T. A., Boustead, G. B. & Hanbury, D. C. Sildenafil influences lower urinary tract symptoms. BJU Int. 90, 836-839 (2002 (Pubitemid 36693615)
69. Liu, L. et al. Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumour cells. J. Pharmacol. Exp. Ther. 299, 583-592 (2001 (Pubitemid 32979671)
70. Andersson, K. E. et al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: Pathophysiology and mechanism(s) of action. Neurourol. Urodyn. 30, 292-301 (2011
71. McVary, K. T., Siegel, R. L. & Carlsson, M. Sildenafil citrate improves erectile function and lower urinary tract symptoms independent of baseline body mass index or LUTS severity. Urology 72, 575-579 (2008
72. Mulhall, J. P., 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. 3, 662-667 (2006
73. McVary, K. T. et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J. Urol. 177, 1401-1407 (2007 (Pubitemid 46435965)
74. McVary, K. T. et al. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: A randomized, double-blind trial. J. Urol. 177, 1071-1077 (2007 (Pubitemid 46216352)
75. Stief, C. G., Porst, H., Neuser, D., Beneke, M. & Ulbrich, E. A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur. Urol. 53, 1236-1244 (2008
76. Gacci, M. et al. Vardenafil improves urodynamic parameters in men with spinal cord injury: Results from a single dose, pilot study. J. Urol. 178, 2040-2044 (2007 (Pubitemid 47538622)
77. Maselli, G. et al. Tadalafil versus solifenacin for persistent storage symptoms after prostate surgery in patients with erectile dysfunction: A prospective randomized study. Int. J. Urol. 18, 515-520 (2011
78. Kaplan, S. A., Gonzalez, R. R. & Te, A. E. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur. Urol. 51, 1717-1723 (2007 (Pubitemid 46634750)
79. Bechara, A. et al. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J. Sex. Med. 5, 2170-2178 (2008
80. Gacci, M. et al. A randomized, placebo-controlled study to assess safety and efficacy of vardenafil 10 mg and tamsulosin 0.4 mg vs. tamsulosin 0.4 mg alone in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. J. Sex. Med. 9, 1624-1633 (2012
81. Taie, K., Moombeini, H., Khazaeli, D. & Salari Panah Firouzabadi, M. Improvement of urodynamic indices by single dose oral tadalafil in men with supra sacral spinal cord injury. Urol. J. 7, 249-253 (2010
82. Tamimi, N. A. et al. A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. BJU Int. 106, 674-680 (2010
83. Giuliano, F. A. et al. A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder. BJU Int. 106, 666-673 (2010
84. Dmochowski, R. et al. Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: A randomized, placebo controlled 12-week clinical trial. J. Urol. 183, 1092-1097 (2010
85. Donatucci, C. F. et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A 1-year, open-label extension study. BJU Int. 107, 1110-1116 (2011
86. Gacci, M. et al. Vardenafil can improve continence recovery after bilateral nerve sparing prostatectomy: Results of a randomized, double blind, placebo-controlled pilot study. J. Sex. Med. 7, 234-243 (2010
87. Sunahara, R. K. & Taussig, R. Isoforms of mammalian adenylyl cyclase: LMultiplicities of signalling. Mol. Interv. 2, 168-184 (2002
88. Cooper, D. M. & Crossthwaite, A. J. Higher-order organization and regulation of adenylyl cyclases. Trends Pharmacol. Sci. 27, 426-431 (2006 (Pubitemid 44069584)
89. Uckert, S., Stief, C. G., Mayer, M., Jonas, U. & Hedlund, P. Distribution and functional significance of phosphodiesterase isoenzymes in the human lower urinary tract. World J. Urol. 23, 368-373 (2005 (Pubitemid 43124387)
90. Truss, M. C., Uckert, S., Stief, C. G., Kuczyk, M. & Jonas, U. Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. I. Identification and characterization. Urol. Res. 24, 123-128 (1996 (Pubitemid 26226247)
91. Andersson, K. E., Chapple, C. & Wein, A. The basis for drug treatment of the overactive bladder. World J. Urol. 19, 294-298 (2001 (Pubitemid 33777073)
92. Gales, B. J. & Gales, M. A. Phosphodiesterase-5 inhibitors for lower urinary tract symptoms in men. Ann. Pharmacother. 42, 111-115 (2008
93. Gomelsky, A. & Dmochowski, R. R. Urodynamic effects of once-daily tadalafil in men with LUTS secondary to clinical BPH. Curr. Urol. Rep. 11, 254-260 (2010
94. Kraus, S. R. et al. Urodynamic standardization in a large-scale, multicentre clinical trial examining the effects of daily tadalafil in men with lower urinary tract symptoms with or without benign prostatic obstruction. Neurourol. Urodyn. 29, 741-747 (2010
95. Oelke, M. et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur. Urol. 61, 917-925 (2012
96. Gacci, M. et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur. Urol. 61, 994-1003 (2012
97. Kaiho, Y. et al. The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction. BJU Int. 101, 615-620 (2008 (Pubitemid 351199275)
98. Sakura, M. et al. Rolipram, a specific type-4 phosphodiesterase inhibitor, inhibits cyclophosphamide-induced haemorrhagic cystitis in rats. BJU Int. 103, 264-269 (2009
99. Shapiro, E., Hartanto, V. & Lepor, H. The response to α blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate 21, 297-307 (1992 (Pubitemid 23045292)
100. Uckert, S., Mayer, M. E., Stief, C. G. & Jonas, U. The future of the oral pharmacotherapy of male erectile dysfunction: Things to come. Exp. Opin. Emerg. Drugs 12, 219-228 (2007 (Pubitemid 46953563)
101. Kuthe, A. et al. Molecular biological characterization of phosphodiesterase 3A from human corpus cavernosum. Chem. Biol. Interact. 119-120, 593-598 (1999 (Pubitemid 29278599)
102. Wheeler, M. A., Ayyagari, R. R., Wheeler, G. L. & Weiss, R. M. Regulation of cyclic nucleotides in the urinary tract. J. Smooth Muscle Res. 41, 1-21 (2005 (Pubitemid 40628355)
103. Fibbi, B. et al. Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract. J. Sex. Med. 7, 59-69 (2010
104. Morelli, A. et al. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 145, 2253-2263 (2004 (Pubitemid 38535054)
105. Abrams, P. et al. The standardisation of terminology in lower urinary tract function: Report from the standardisation sub-committee of the International Continence Society. Urology 61, 37-49 (2003 (Pubitemid 36151708)
106. Abrams, P. et al. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and faecal incontinence. Neurourol. Urodyn. 29, 213-240 (2010