Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Treatment of Peyronie's disease with PDE5 inhibitors: an antifibrotic strategy

Nature Reviews Urology volume 7, pages 215–221 (2010)Cite this article

Subjects

Abstract

Peyronie's disease (PD) is a localized fibrotic condition of the tunica albuginea that is associated with risk factors for corpora cavernosa fibrosis (such as advanced age and diabetes) and Dupuytren contracture, another localized fibrotic process. Most of the current pharmacological treatments for PD are not based on antifibrotic approaches that have shown promising results in animal models and clinical efficacy in other fibrotic conditions, which may explain why they are generally unsuccessful. Evidence gathered in human specimens and animal models of PD have elucidated aspects of its etiology and histopathology, showing that overexpression of transforming growth factor β1, plasminogen activator inhibitor 1, reactive oxygen species and other profibrotic factors, which are, in most cases, assumed to be induced by trauma to the tunica albuginea, leads to myofibroblast accumulation and excessive deposition of collagen. At the same time, a steady overexpression of inducible nitric oxide synthase, leading to increased nitric oxide and cGMP levels, seems to act as an endogenous antifibrotic mechanism. This process has also been reported in corporal and cardiovascular fibrosis, and has led to the demonstration that long-term continuous administration of phosphodiesterase type 5 inhibitors counteracts the development of a PD-like fibrotic plaque in a rat model, and later extended to the prevention of corporal fibrosis in animal models of erectile dysfunction.

Key Points

  • Rodent models of Peyronie's disease (PD) are representative of most of the main histological and biochemical features present in human specimens

  • Cell cultures obtained from the human PD plaque and its rat counterpart have added to the experimental evidence acquired in the human and in animal models

  • Endogenous mechanisms of defense against tunical tissue inflammation, oxidative stress and fibrosis have been detected in the PD plaque and the rat PD-like lesion, and may be mimicked pharmacologically for treatment

  • Endogenously elicited inducible nitric oxide synthase leads to sustained production of nitric oxide and cGMP, which counteract myofibroblast differentiation, accumulation of reactive oxygen species, cytokine release, and collagen deposition

  • Continuous long-term administration of nitric oxide donors and phosphodiesterase 5 inhibitors has shown preventive and corrective effects in a rat model of PD: studies in patients with PD are now needed

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of the etiology and pathophysiology of the fibrotic process leading to the Peyronie disease plaque (red), and the antifibrotic effects (green) of endogenous iNOS.

Similar content being viewed by others

References

  1. Gonzalez-Cadavid, N. F. & Rajfer, J. in Current Clinical Urology: Peyronie's Disease, A Guide to Clinical Management (ed. Levine, L. A. ) 19–39 (Humana Press, Totowa, 2007).

    Google Scholar 

  2. Smith, J. F., Walsh, T. J. & Lue, T. F. Peyronie's disease: a critical appraisal of current diagnosis and treatment. Int. J. Impot. Res. 20, 445–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Müller, A. & Mulhall, J. P. Peyronie's disease intervention trials: methodological challenges and issues. J. Sex. Med. 6, 848–861 (2009).

    Article  PubMed  Google Scholar 

  4. Smith, C. J., McMahon, C. & Shabsigh, R. Peyronie's disease: the epidemiology, aetiology and clinical evaluation of deformity. BJU Int. 95, 729–732 (2005).

    Article  PubMed  Google Scholar 

  5. Mulhall, J. P. 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. 171, 2350–2353 (2004).

    Article  PubMed  Google Scholar 

  6. Taylor, F. L. & Levine, L. A. Peyronie's disease. Urol. Clin. North Am. 34, 517–534 (2007).

    Article  PubMed  Google Scholar 

  7. Carrieri, M. P., Serraino, D., Palmiotto, F., Nucci, G. & Sasso, F. A case–control study on risk factors for Peyronie's disease. J. Clin. Epidemiol. 51, 511–515 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Deveci, S. et al. Defining the clinical characteristics of Peyronie's disease in young men. J. Sex. Med. 4, 485–490 (2007).

    Article  PubMed  Google Scholar 

  9. Bjekic, M. D., Vlajinac, H. D., Sipetic, S. B. & Marinkovic, J. M. Risk factors for Peyronie's disease: a case–control study. BJU Int. 97, 570–574 (2006).

    Article  PubMed  Google Scholar 

  10. Gonzalez-Cadavid, N. F. & Rajfer, J. Experimental models of Peyronie's disease. Implications for new therapies. J. Sex. Med. 6, 303–313 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Valente, E. G. et al. L-Arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie's fibrotic plaque and related fibroblast cultures. Nitric Oxide 9, 229–244 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Devine, C. J. Jr, Somers, K. D., Jordan, S. G. & Schlossberg, S. M. Proposal: trauma as the cause of the Peyronie's lesion. J. Urol. 157, 285–290 (1997).

    Article  PubMed  Google Scholar 

  13. Somers, K. D. & Dawson, D. M. Fibrin deposition in Peyronie's disease plaque. J. Urol. 157, 311–315 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Davila, H. H., Magee, T. R., Zuniga, F. I., Rajfer, J. & Gonzalez-Cadavid, N. F. Peyronie's disease associated with increase in plasminogen activator inhibitor in fibrotic plaque. Urology 65, 645–648 (2005).

    Article  PubMed  Google Scholar 

  15. Davila, H. H., Ferrini, M. G., Rajfer, J. & Gonzalez-Cadavid, N. F. Fibrin as an inducer of fibrosis in the tunica albuginea of the rat: a new animal model of Peyronie's disease. BJU Int. 91, 830–838 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Ehrlich, H. P. Scar contracture: cellular and connective tissue aspects in Peyronie's disease. J. Urol. 157, 316–319 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Davila, H. H., Magee, T. R., Vernet, D., Rajfer, J. & Gonzalez-Cadavid, N. F. Gene transfer of inducible nitric oxide synthase complementary DNA regresses the fibrotic plaque in an animal model of Peyronie's disease. Biol. Reprod. 71, 1568–1577 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Usta, M. F. et al. Relationship between the severity of penile curvature and the presence of comorbidities in men with Peyronie's disease. J. Urol. 171, 775–779 (2004).

    Article  PubMed  Google Scholar 

  19. Perimenis, P., Athanasopoulos, A., Gyftopoulos, K., Katsenis, G. & Barbalias, G. Peyronie's disease: epidemiology and clinical presentation of 134 cases. Int. Urol. Nephrol. 32, 691–694 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. El-Sakka, A. I., Selph, C. A., Yen, T. S., Dahiya, R. & Lue, T. F. The effect of surgical trauma on rat tunica albuginea. J. Urol. 159, 1700–1707 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Schiavino, D. et al. Immunologic findings in Peyronie's disease: a controlled study. Urology 50, 764–768 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Noss, M. B., Day, N. S., Christ, G. J. & Melman, A. The genetics and immunology of Peyronie's disease. Int. J. Impot. Res. 12 (Suppl. 4), S127–S132 (2000).

    Article  PubMed  Google Scholar 

  23. Hauck, E. W., Hauptmann, A., Weidner, W., Bein, G. & Hackstein, H. Prospective analysis of HLA classes I and II antigen frequency in patients with Peyronie's disease. J. Urol. 170, 1443–1446 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Anafarta, K., Bedük, Y., Uluoglu, O., Aydos, K. & Baltaci, S. The significance of histopathological changes of the normal tunica albuginea in Peyronie's disease. Int. Urol. Nephrol. 26, 71–77 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Ferrini, M. G. et al. Antifibrotic role of inducible nitric oxide synthase. Nitric Oxide 6, 283–294 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807–1816 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Eyden, B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J. Cell. Mol. Med. 12, 2022–2037 (2008).

    Google Scholar 

  28. Somers, K. D. et al. Cell culture of Peyronie's disease plaque and normal penile tissue. J. Urol. 127, 585–588 (1982).

    Article  CAS  PubMed  Google Scholar 

  29. Mulhall, J. P., Anderson, M. S., Lubrano, T. & Shankey, T. V. Peyronie's disease cell culture models: phenotypic, genotypic and functional analyses. Int. J. Impot. Res. 14, 397–405 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Vernet, D. et al. Effect of nitric oxide on the differentiation of fibroblasts into myofibroblasts in the Peyronie's fibrotic plaque and in its rat model. Nitric Oxide 7, 262–276 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Vernet, D. et al. Evidence that osteogenic progenitor cells in the human tunica albuginea may originate from stem cells: implications for peyronie disease. Biol. Reprod. 73, 1199–1210 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Vernet, D. et al. Phosphodiesterase type 5 is not upregulated by tadalafil in cultures of human penile cells. J. Sex. Med. 3, 84–94 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Vande Berg, J. S. et al. Mechanisms of calcification in Peyronie's disease. J. Urol. 127, 52–54 (1982).

    Article  CAS  PubMed  Google Scholar 

  34. Kadioglu, A. et al. A retrospective review of 307 men with Peyronie's disease. J. Urol. 168, 1075–1079 (2002).

    Article  PubMed  Google Scholar 

  35. Wynn, T. A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. El-Sakka, A. I., Hassoba, H. M., Pillarisetty, R. J., Dahiya, R. & Lue, T. F. Peyronie's disease is associated with an increase in transforming growth factor-beta protein expression. J. Urol. 158, 1391–1394 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. El-Sakka, A. I. et al. An animal model of Peyronie's-like condition associated with an increase of transforming growth factor beta mRNA and protein expression. J. Urol. 158, 2284–2290 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. El-Sakka, A. I. et al. Histological and ultrastructural alterations in an animal model of Peyronie's disease. Br. J. Urol. 81, 445–452 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Bivalacqua, T. J. et al. A rat model of Peyronie's disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression. J. Urol. 163, 1992–1998 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Ferrini, M. G., Kovanecz, I., Nolazco, G., Rajfer, J. & Gonzalez-Cadavid, N. F. Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease. BJU Int. 97, 625–633 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Cantini, L. P. et al. Profibrotic role of myostatin in Peyronie's disease. J. Sex. Med. 5, 1607–1622 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Piao, S. et al. Repeated intratunical injection of adenovirus expressing transforming growth factor-β1 in a rat induces penile curvature with tunical fibrotic plaque: a useful model for the study of Peyronie's disease. Int. J. Androl. 31, 346–353 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Rajfer, J., Gore, J. L., Kaufman, J. & Gonzalez-Cadavid, N. Case report: avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide. J. Sex. Med. 3, 173–176 (2006).

    Article  PubMed  Google Scholar 

  44. Lucattelli, M. et al. A new mouse model of Peyronie's disease: an increased expression of hypoxia-induciblefactor-1 target genes during the development of penile changes. Int. J. Biochem. Cell Biol. 40, 2638–2648 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Nolazco, G. et al. Effect of muscle-derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat. BJU Int. 101, 1156–1164 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Mulhall, J. P. Expanding the paradigm for plaque development in Peyronie's disease. Int. J. Impot. Res. 15 (Suppl. 5), S93–S102 (2003).

    Article  PubMed  Google Scholar 

  47. Mulhall, J. P. et al. Peyronie's disease fibroblasts demonstrate tumorigenicity in the severe combined immunodeficient (SCID) mouse model. Int. J. Impot. Res. 16, 99–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Gonzalez-Cadavid, N. F. & Rajfer, J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie's disease. Nat. Clin. Pract. Urol. 2, 291–297 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Gonzalez-Cadavid, N. F. Mechanisms of penile fibrosis. J. Sex. Med. 6 (Suppl. 3), 353–362 (2009).

    Article  PubMed  Google Scholar 

  50. Nehra, A. & Nylhall, J. Peyronie's disease. In Standard Practice in Sexual Medicine 1st edn (eds Porst, H. & Buvat, J.) 158–173 (Blackwell, Malden, 2006).

    Chapter  Google Scholar 

  51. Mulhall, J. P. Expanding the paradigm for plaque development in Peyronie's disease. Int. J. Impot. Res. 15 (Suppl. 5), S93–S102 (2003).

    Article  PubMed  Google Scholar 

  52. Del Carlo, M., Cole, A. A. & Levine, L. A. Differential calcium independent regulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases by interleukin-1β and transforming growth factor-β in Peyronie's plaque fibroblasts. J. Urol. 179, 2447–2455 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Magee, T. R. et al. Gene expression profiles in the Peyronie's disease plaque. Urology 59, 451–457 (2002).

    Article  PubMed  Google Scholar 

  54. Qian, A., Meals, R. A., Rajfer, J. & Gonzalez-Cadavid, N. F. Comparison of gene expression profiles between Peyronie's disease and Dupuytren's contracture. Urology 64, 399–404 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Hellstrom, W. Medical management of Peyronie's disease. J. Androl. 30, 397–404 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Sivakumar, P. & Das, A. M. Fibrosis, chronic inflammation and new pathways for drug discovery. Inflamm. Res. 57, 410–418 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Gonzalez-Cadavid, N. F. & Rajfer, J. The pleiotropic effects of inducible nitric oxide synthase on the physiology and pathology of penile erection. Curr. Pharm. Des. 11, 4041–4046 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Ferrini, M. G., Davila, H., Valente, E. G., Gonzalez-Cadavid, N. F. & Rajfer, J. Aging-related induction of inducible nitric oxide synthase (iNOS) is vasculo-protective in the arterial media. Cardiovasc. Res. 61, 796–805 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Ferrini, M. G. et al. Long-term continuous treatment with vardenafil prevents fibrosis and preserves smooth muscle content in the rat corpora cavernosa after bilateral cavernosal nerve transection. Urology 68, 429–435 (2006).

    Article  PubMed  Google Scholar 

  60. Ferrini, M. G. et al. Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat. Biol. Reprod. 76, 915–923 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Kovanecz, I. et al. Long term sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats. Int. J. Impot. Res. 100, 867–874 (2007).

    CAS  Google Scholar 

  62. Kovanecz, I. et al. Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction (CVOD) that occurs following cavernosal nerve resection in the rat. BJU Int. 101, 203–210 (2008).

    CAS  PubMed  Google Scholar 

  63. Ferrini, M. G. et al. Fibrosis and loss of smooth muscle in the corpora cavernosa precede corporal veno-occlusive dysfunction (CVOD) induced by experimental cavernosal nerve damage in the rat. J. Sex. Med. 6, 415–428 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Ferrini, M. G. et al. The genetic inactivation of inducible nitric oxide synthase intensifies fibrosis and oxidative stress in the penile corpora cavernosa in type 1 diabetes. J. Sex. Med. (in press).

  65. Hochberg, D. et al. Interstitial fibrosis of unilateral ureteral obstruction is exacerbated in kidneys of mice lacking the gene for inducible nitric oxide synthase. Lab. Invest. 80, 1721–1728 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Trachtman, H., Futterweit, S., Pine, E., Mann, J. & Valderrama, E. Chronic diabetic nephropathy: role of inducible nitric oxide synthase. Pediatr. Nephrol. 17, 20–29 (2002).

    Article  PubMed  Google Scholar 

  67. Chen, Y. et al. Deficiency of inducible nitric oxide synthase exacerbates hepatic fibrosis in mice fed high-fat diet. Biochem. Biophys. Res. Commun. 326, 45–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Aram, G., Potter, J. J., Liu, X., Torbenson, M. S. & Mezey, E. Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration. Hepatology 47, 2051–2058 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Bayir, H. et al. Enhanced oxidative stress in iNOS deficient mice after traumatic brain injury: support for a neuroprotective role of iNOS. J. Cereb. Blood Flow Metab. 25, 673–684 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Park, K. M. et al. Inducible nitric-oxide synthase is an important contributor to prolonged protective effects of ischemic preconditioning in the mouse kidney. J. Biol. Chem. 278, 27256–27266 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Jones, S. P. & Bolli, R. The ubiquitous role of nitric oxide in cardioprotection. J. Mol. Cell. Cardiol. 40, 16–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Hesse, M., Cheever, A. W., Jankovic, D. & Wynn, T. A. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model 0f granulomatous disease. Am. J. Pathol. 157, 945–955 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang, P. et al. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ. Res. 100, 1089–1098 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lu, L., Chen, S. S., Hassid, A. & Sun, Y. Cardiac fibrogenesis following infarction in mice with deletion of inducible nitric oxide synthase. Am. J. Med. Sci. 335, 431–438 (2008).

    Article  PubMed  Google Scholar 

  75. Kadkhodaee, M. et al. Proteinuria is reduced by inhibition of inducible nitric oxide synthase in rat renal ischemia-reperfusion injury. Transplant. Proc. 41, 2907–2909 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Kuhlencordt, P. J., Chen, J., Han, F., Astern, J. & Huang, P. L. Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Circulation 103, 3099–3104 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Toblli, J. E. et al. Antifibrotic effects of pioglitazone on the kidney in a rat model of type 2 diabetes mellitus. Nephrol. Dial. Transplant. 24, 2384–2391 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mookerjee, I. et al. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J. 23, 1219–1229 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Vyas-Read, S., Shaul, P. W., Yuhanna, I. S. & Willis, B. C. Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L212–L221 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Brosius, F. C. 3rd. New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy. Rev. Endocr. Metab. Disord. 9, 245–254 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kalk, P. et al. Pulmonary fibrosis in L-NAME-treated mice is dependent on an activated endothelin system. Can. J. Physiol. Pharmacol. 86, 541–545 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Peters, H. et al. NO mediates antifibrotic actions of L-arginine supplementation following induction of anti-thy1 glomerulonephritis. Kidney Int. 64, 509–518 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Dunkern, T. R., Feurstein, D., Rossi, G. A., Sabatini, F. & Hatzelmann, A. Inhibition of TGF-β induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. Eur. J. Pharmacol. 572, 12–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Masuyama, H. et al. Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. Hypertens. Res. 32, 597–603 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Sawada, N. et al. Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and anti-fibrotic signals in blood vessels. Mol. Cell. Biol. 29, 6018–6032 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Knorr, A. et al. Nitric oxide-independent activation of soluble guanylate cyclase by BAY 60–2770 in experimental liver fibrosis. Arzneimittelforschung 58, 71–80 (2008).

    CAS  PubMed  Google Scholar 

  87. Wang-Rosenke, Y., Neumayer, H. H. & Peters, H. NO signaling through cGMP in renal tissue fibrosis and beyond: key pathway and novel therapeutic target. Curr. Med. Chem. 15, 1396–1406 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Iacono, F. et al. Histopathologically proven prevention of post-prostatectomy cavernosal fibrosis with sildenafil. Urol. Int. 80, 249–252 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Vignozzi, L. et al. Effect of sildenafil administration on penile hypoxia induced by cavernous neurotomy in the rat. Int. J. Impot. Res. 20, 60–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Magheli, A. & Burnett, A. L. Erectile dysfunction following prostatectomy: prevention and treatment. Nat. Rev. Urol. 6, 415–427 (2009).

    Article  PubMed  Google Scholar 

  91. Hemnes, A. R., Zaiman, A. & Champion, H. C. PDE 5A 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. 294, L24–L33 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Wang, Y. et al. Enhancing cGMP in experimental progressive renal fibrosis: soluble guanylate cyclase stimulation vs. phosphodiesterase inhibition. Am. J. Physiol. Renal Physiol. 290, F167–F176 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Nagayama, T. 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. 53, 207–215 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Radovits, T. et al. The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus. Br. J. Pharmacol. 156, 909–919 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hohenstein, B., Daniel, C., Wittmann, S. & Hugo, C. PDE-5 inhibition impedes TSP-1 expression, TGF-β activation and matrix accumulation in experimental glomerulonephritis. Nephrol. Dial. Transplant. 23, 3427–3436 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Steiropoulos, P., Trakada, G. & Bouros, D. Current pharmacological treatment of pulmonary arterial hypertension. Curr. Clin. Pharmacol. 3, 11–19 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Levine, L. A. & Latchamsetty, K. C. Treatment of erectile dysfunction in patients with Peyronie's disease using sildenafil citrate. Int. J. Impot. Res. 14, 478–482 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Porst, H. et al. Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction. J. Sex. Med. 5, 2160–2169 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Bella, A. J., Deyoung, L. X., Al-Numi, M. & Brock, G. B. Daily administration of phosphodiesterase type 5 inhibitors for urological and nonurological indications. Eur. Urol. 52, 990–1005 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to primarily acknowledge the Eli and Edythe Broad Foundation, without whose initial support none of the experimental research work on PD at the UCLA group would have been possible. Additional funding was subsequently applied for some aspects of this research from NIH R01DK-53069, NIH R21DK-070003, Department of Defense PR064756, and NIH G12RR-03026.

Author information

Authors and Affiliations

  1. Department of Urology, David Geffen School of Medicine at UCLA, and Los Angeles Biomedical Research Institute (LABioMed) at Harbor-UCLA Medical Center, Building F-6, 1124 West Carson Street, Torrance, 90502, CA, USA

    Nestor F. Gonzalez-Cadavid & Jacob Rajfer

Authors
  1. Nestor F. Gonzalez-Cadavid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacob Rajfer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nestor F. Gonzalez-Cadavid.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonzalez-Cadavid, N., Rajfer, J. Treatment of Peyronie's disease with PDE5 inhibitors: an antifibrotic strategy. Nat Rev Urol 7, 215–221 (2010). https://doi.org/10.1038/nrurol.2010.24

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2010.24

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing