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The role of phosphodiesterases in bladder pathophysiology

Abstract

Nitric oxide and the cyclic nucleotide monophosphates cAMP and cGMP have a role in control of the micturition process and hence, are suggested to be involved in the pathophysiology of storage and voiding disorders. Phosphodiesterase enzymes (PDEs) hydrolyse cAMP and cGMP. Inhibition of PDEs increases cAMP and cGMP levels and relaxes urinary bladder smooth musculature. Although many preclinical studies have been conducted, to date, only PDE1 and PDE5 inhibitors have been tested clinically for the management of storage and voiding disorders. Treatment with PDE1 inhibitors might improve micturition frequency in patients with overactive bladder, whereas inhibition of PDE5 improves lower urinary tract symptoms in men, either with or without BPH and erectile dysfunction (ED). Furthermore, the combination of a PDE5 inhibitor and an α-adrenoceptor antagonist has superior efficacy to monotherapy with either agent. However, the role of PDE5 inhibitors in the treatment of women with detrusor overactivity remains unclear. The clinical application of agents that inhibit other PDEs, including PDE4, also certainly merits scientific attention. PDE inhibitors seem likely to become a valuable alternative treatment for patients with storage and voiding disorders in the future.

Key Points

  • Phosphodiesterases (PDEs) hydrolyse cAMP and cGMP, and are thought to have a crucial role in bladder physiology

  • Inhibition of PDEs raises cAMP and cGMP levels and relaxes urinary bladder muscles

  • Although PDEs 1–5 and 7–9 occur in the human urinary bladder, only PDE1 and PDE5 inhibitors have been clinically tested for the treatment of storage and voiding disorders

  • PDE1 inhibition improves micturition frequency

  • PDE5 inhibition alleviates lower urinary tract symptoms in men, including those with and without BPH and erectile dysfunction

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Figure 1: Schematic diagram of the cyclic nucleotide signalling pathways.
Figure 2: A schematic overview of the different PDE isoenzymes and some of their characteristics, including affinity for cAMP and cGMP.
Figure 3: Phosphodiesterases and innervation in the male lower urinary tract.

References

  1. 1

    Beavo, J. A. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75, 725–748 (1995).

    CAS  Article  PubMed  Google Scholar 

  2. 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).

    CAS  Article  PubMed  Google Scholar 

  3. 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).

    CAS  Article  PubMed  Google Scholar 

  4. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Dessauer, C. W. Adenylyl cyclase—A-kinase anchoring protein complexes: the next dimension in cAMP signalling. Mol. Pharmacol. 76, 935–941 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Lucas, K. A. et al. Guanylyl cyclases and signalling by cyclic GMP. Pharmacol. Rev. 52, 375–414 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Moncada, S., Palmer, R. M. & Higgs, E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109–142 (1991).

    CAS  PubMed  Google Scholar 

  8. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Uckert, S. et al. Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: present and future. Eur. Urol. 50, 1194–1207 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Gillespie, J. I. Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated bladder. BJU Int. 93, 1325–1332 (2004).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Hanna-Mitchell, A. T. & Birder, L. A. New insights into the pharmacology of the bladder. Curr. Opin. Urol. 18, 347–352 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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).

    CAS  Article  PubMed  Google Scholar 

  15. 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).

    CAS  Article  PubMed  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    CAS  Article  PubMed  Google Scholar 

  18. 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).

    CAS  Article  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    CAS  Article  PubMed  Google Scholar 

  21. 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).

    CAS  Article  PubMed  Google Scholar 

  22. 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).

    CAS  Article  PubMed  Google Scholar 

  23. 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).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Uckert, S. & Oelke, M. Phosphodiesterase (PDE) inhibitors in the treatment of lower urinary tract dysfunction. Br. J. Clin. Pharmacol. 72, 197–204 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Essayan, D. M. Cyclic nucleotide phosphodiesterases. J. Allergy Clin. Immunol. 108, 671–680 (2001).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Essayan, D. M. Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem. Pharmacol. 57, 965–973 (1999).

    CAS  Article  PubMed  Google Scholar 

  27. 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).

    CAS  Article  PubMed  Google Scholar 

  28. 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).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Conti, M. & Jin, S. L. The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 63, 1–38 (1999).

    CAS  Article  PubMed  Google Scholar 

  30. 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).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Filippi, S. et al. Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 148, 1019–1029 (2007).

    CAS  Article  Google Scholar 

  32. 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. 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).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Morley, D. J. et al. Distribution of phosphodiesterase I in normal human tissues. J. Histochem. Cytochem. 35, 75–82 (1987).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Nagasaki, S. et al. Phosphodiesterase type 9 (PDE9) in the human lower urinary tract: an immunohistochemical study. BJU Int. 109, 934–940 (2012).

    CAS  Article  PubMed  Google Scholar 

  36. 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).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Kuthe, A. et al. Gene expression of the phosphodiesterases 3A and 5A in human corpus cavernosum penis. Eur. Urol. 38, 108–114 (2000).

    CAS  Article  PubMed  Google Scholar 

  38. 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).

    Article  PubMed  Google Scholar 

  39. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  Article  PubMed  Google Scholar 

  41. 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).

    CAS  Article  PubMed  Google Scholar 

  42. 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).

    CAS  Article  PubMed  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. 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).

    CAS  Article  PubMed  Google Scholar 

  45. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  Article  PubMed  Google Scholar 

  47. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    CAS  Article  PubMed  Google Scholar 

  50. 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).

    CAS  Article  PubMed  Google Scholar 

  51. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Morelli, A. et al. Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J. Sex. Med. 7, 107–120 (2010).

    CAS  Article  PubMed  Google Scholar 

  53. 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).

    CAS  Article  PubMed  Google Scholar 

  54. 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).

    CAS  Article  PubMed  Google Scholar 

  55. 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).

    CAS  Article  PubMed  Google Scholar 

  56. 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).

    CAS  Article  PubMed  Google Scholar 

  57. 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).

    CAS  Article  PubMed  Google Scholar 

  58. 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).

    CAS  Article  PubMed  Google Scholar 

  59. 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).

    CAS  Article  PubMed  Google Scholar 

  60. 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).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Bittencourt, J. A. et al. Relaxant effects of sildenafil on the human isolated bladder neck. Urology 73, 427–430 (2009).

    Article  PubMed  Google Scholar 

  62. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 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).

    Article  Google Scholar 

  64. 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).

    CAS  Article  PubMed  Google Scholar 

  65. 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).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Hatzimouratidis, K. Sildenafil in the treatment of erectile dysfunction: an overview of the clinical evidence. Clin. Interv. Aging 1, 403–414 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 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).

    Article  PubMed  Google Scholar 

  68. 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).

    CAS  Article  PubMed  Google Scholar 

  69. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    CAS  Article  PubMed  Google Scholar 

  71. 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).

    Article  PubMed  Google Scholar 

  72. 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).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    McVary, K. T. et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J. Urol. 177, 1401–1407 (2007).

    CAS  Article  PubMed  Google Scholar 

  74. 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).

    CAS  Article  PubMed  Google Scholar 

  75. 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).

    CAS  Article  PubMed  Google Scholar 

  76. 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).

    CAS  Article  PubMed  Google Scholar 

  77. 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).

    CAS  Article  PubMed  Google Scholar 

  78. 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).

    CAS  Article  PubMed  Google Scholar 

  79. 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).

    CAS  Article  PubMed  Google Scholar 

  80. 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).

    CAS  Article  PubMed  Google Scholar 

  81. 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).

    PubMed  PubMed Central  Google Scholar 

  82. 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).

    CAS  Article  PubMed  Google Scholar 

  83. 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).

    CAS  Article  PubMed  Google Scholar 

  84. 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).

    CAS  Article  PubMed  Google Scholar 

  85. 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).

    Article  PubMed  Google Scholar 

  86. 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).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Sunahara, R. K. & Taussig, R. Isoforms of mammalian adenylyl cyclase: multiplicities of signalling. Mol. Interv. 2, 168–184 (2002).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Cooper, D. M. & Crossthwaite, A. J. Higher-order organization and regulation of adenylyl cyclases. Trends Pharmacol. Sci. 27, 426–431 (2006).

    CAS  Article  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Andersson, K. E., Chapple, C. & Wein, A. The basis for drug treatment of the overactive bladder. World J. Urol. 19, 294–298 (2001).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Gales, B. J. & Gales, M. A. Phosphodiesterase-5 inhibitors for lower urinary tract symptoms in men. Ann. Pharmacother. 42, 111–115 (2008).

    CAS  Article  PubMed  Google Scholar 

  93. 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).

    Article  PubMed  Google Scholar 

  94. 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).

    CAS  Article  PubMed  Google Scholar 

  95. 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).

    CAS  Article  PubMed  Google Scholar 

  96. 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).

    CAS  Article  PubMed  Google Scholar 

  97. 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).

    CAS  Article  PubMed  Google Scholar 

  98. 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).

    CAS  Article  PubMed  Google Scholar 

  99. 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).

    CAS  Article  PubMed  Google Scholar 

  100. 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).

    Article  Google Scholar 

  101. 101

    Kuthe, A. et al. Molecular biological characterization of phosphodiesterase 3A from human corpus cavernosum. Chem. Biol. Interact. 119–120, 593–598 (1999).

    Article  PubMed  Google Scholar 

  102. 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).

    Article  PubMed  Google Scholar 

  103. 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).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    Morelli, A. et al. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 145, 2253–2263 (2004).

    CAS  Article  PubMed  Google Scholar 

  105. 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).

    Article  Google Scholar 

  106. 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).

    CAS  Article  PubMed  Google Scholar 

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M. S. Rahnama'i wrote the article. In addition, M. S. Rahnamai and R. Hohnen researched the data for the article, and M. S. Rahnama'i, S. Ückert and G. A. van Koeveringe contributed substantially to discussions of the content and review or editing of the manuscript before submission.

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Correspondence to Mohammad S. Rahnama'i.

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Rahnama'i, M., Ückert, S., Hohnen, R. et al. The role of phosphodiesterases in bladder pathophysiology. Nat Rev Urol 10, 414–424 (2013). https://doi.org/10.1038/nrurol.2013.101

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