Skip to main content
Log in

The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms

  • Topic Paper
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Abstract

To date, there is an increasing interest in the nitric oxide (NO) pathway as a potential pharmacological target to treat male lower urinary tract symptomatology (LUTS). In the transition zone of the human prostate, a dense nitrinergic innervation has been shown of the fibromuscular stroma, glandular epithelium and blood vessels. The expression of key proteins of the NO pathway, such as the endothelial and neuronal nitric oxide synthase (eNOS, nNOS), cGMP-degrading phosphodiesterase type 5 (PDE5) and cGMP-binding protein kinase (cGK), has also been demonstrated. The hypothesis that an impaired NO/cGMP-signaling may contribute to the pathophysiology of benign prostatic hyperplasia (BPH) is supported by the results from randomized, placebo-controlled clinical studies, indicating that NO donor drugs and PDE5-inhibitors sildenafil, tadalafil and vardenafil may be useful to treat storage and voiding dysfunctions resulting from LUTS in men. Thus, given a potential role of the NO-pathway in the prostate and/or in other parts of lower urinary tract (e.g. bladder), the enhancement of the NO signaling by NO donor drugs, PDE5 inhibitors or activators of the soluble guanylyl cyclase (sGC) may represent a new therapeutic strategy for the treatment of LUTS. This review serves to focus on the role of NO and the NO-dependent signaling in the control of smooth muscle function in the human prostate. Results from clinical trials in men with LUTS/BPH are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142

    PubMed  CAS  Google Scholar 

  2. Andersson KE, Persson K (1994) Nitric oxide synthase and nitric oxide-mediated effects in lower urinary tract smooth muscles. World J Urol 12:274–280

    PubMed  CAS  Google Scholar 

  3. Andersson KE (2001) Pharmacology of penile erection. Pharmacol Rev 53:417–450

    PubMed  CAS  Google Scholar 

  4. Andersson KE, Persson K (1995) Nitric oxide synthase and the lower urinary tract: possible implications for physiology and pathophysiology. Scand J Urol Nephrol 175(Suppl):43–53

    CAS  Google Scholar 

  5. Hedlund P (2005) Nitric oxide/cGMP-mediated effects in the outflow region of the lower urinary tract - is there a basis for pharmacological targeting of cGMP? World J Urol 23:362–367

    Article  PubMed  CAS  Google Scholar 

  6. Andersson KE (2007) LUTS treatment: future treatment options. Neurourol Urodyn 26:928–933

    Article  PubMed  CAS  Google Scholar 

  7. Förstermann U, Closs EI, Pollack JS, Nakane M, Schwarz P, Gath I, Kleinert H (1994) Nitric oxide synthase isoenzymes: characterization, purification, molecular cloning and functions. Hypertension 23:1112–1131

    Google Scholar 

  8. Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP (2000) Molecular mechanism of cGMP-mediated smooth muscle relaxation. J Cell Physiol 184:409–420

    Article  PubMed  CAS  Google Scholar 

  9. Ückert S, Hedlund P, Andersson KE, Truss MC, Jonas U, Stief CG (2006) Update on phosphodiesterase (PDE) isoenzymes as pharmacological targets in urology: present and future. Eur Urol 50:1194–1207

    Article  PubMed  Google Scholar 

  10. Burnett AL, Maguire MP, Chamness SL, Ricker DD, Takeda M, Lepor H, Chang TSK (1995) Characterization and localization of nitric oxide synthase in the human prostate. Urology 45:435–439

    Article  PubMed  CAS  Google Scholar 

  11. Bloch W, Klotz T, Loch C, Schmidt G, Engelmann U, Addicks K (1997) Distribution of nitric oxide synthase implies a regulation of circulation, smooth muscle tone, and secretory function in the human prostate by nitric oxide. Prostate 33:1–8

    Article  PubMed  CAS  Google Scholar 

  12. Sjöstrand NO, Ehren I, Eldh J, Wiklund NP (1998) NADPH-diaphorase in glandular cells and nerves and its relation to acetylcholinesterase-positive nerves in the male reproductive tract of man and guinea-pig. Urol Res 26:181–188

    Article  PubMed  Google Scholar 

  13. Hedlund P, Ekstrom P, Larsson B, Alm P, Andersson KE (1997) Heme oxygenase and NO-synthase in the human prostate - relation to adrenergic, cholinergic and peptide-containing nerves. J Auton Nerv Syst 63:115–126

    Article  PubMed  CAS  Google Scholar 

  14. Richter K, Heuer O, Ückert S, Stief CG, Jonas U, Wolf G (2004) Immunocytochemical distribution of nitric oxide synthases in the human prostate. J Urol 171(Suppl 4):347 (abstract)

    Google Scholar 

  15. Gradini R, Realacci M, Ginepri A, Naso G, Santangelo C, Cela O, Sale P, Berardi A, Petrangeli E, Gallucci M, di Silverio F, Russo MA (1999) Nitric oxide synthases in normal and benign hyperplastic human prostate: immunohistochemistry and molecular biology. J Pathol 189:224–229

    Article  PubMed  CAS  Google Scholar 

  16. Luo J, Dunn T, Ewing C, Sauvageot J, Chen Y, Trent J, Isaacs W (2002) Gene expression signature of benign prostatic hyperplasia revealed by cDNA microarray analysis. Prostate 51:189–200

    Article  PubMed  CAS  Google Scholar 

  17. Aikawa K, Yokota T, Okamura H, Yamaguchi O (2001) Endogenous nitric oxide-mediated relaxation and nitrinergic innervation in the rabbit prostate: the changes with aging. Prostate 48:40–46

    Article  PubMed  CAS  Google Scholar 

  18. Klotz T, Bloch W, Volberg C, Engelmann U, Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82:1897–1903

    Article  PubMed  CAS  Google Scholar 

  19. Baltaci S, Orhan D, Gögüs C, Türkölmez K, Tulunay Ö, Gögüs O (2001) Inducible nitric oxide synthase expression in benign prostatic hyperplasia, low- and high-grade prostatic intraepithelial neoplasia and prostatic carcinoma. BJU Int 88:100–103

    Article  PubMed  CAS  Google Scholar 

  20. Vaandrager AB, de Jonge HR (1996) Signalling by cGMP-dependent protein kinases. Mol Cell Biochem 157:23–30

    Article  PubMed  CAS  Google Scholar 

  21. Haynes JM, Cook ALM (2006) Protein kinase G-induced activation of KATP channels reduces contractility of human prostate tissue. Prostate 66:377–385

    Article  PubMed  CAS  Google Scholar 

  22. Waldkirch ES, Ückert S, Langnäse K, Richter K, Jonas U, Wolf G, Andersson KE, Stief CG, Hedlund P (2007) Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1 in human prostate tissue. Eur Urol 52:495–502

    Article  PubMed  CAS  Google Scholar 

  23. Ückert S, Küthe A, Jonas U, Stief CG (2001) Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol 166:2484–2490

    Article  PubMed  Google Scholar 

  24. Ückert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P (2006) Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 49:740–745

    Article  PubMed  Google Scholar 

  25. Takeda M, Tang R, Shapiro E, Burnett AL, Lepor H (1995) Effects of nitric oxide on human and canine prostates. Urology 45:440–446

    Article  PubMed  CAS  Google Scholar 

  26. Kedia G, Ückert S, Scheller F, Chigogidze T, Managadze L, Jonas U, Truss MC (2006) In vitro functional responses of isolated normal human prostatic tissue to compounds interacting with the cyclic guanosine monophosphate pathway. Urology 67:1292–1297

    Article  PubMed  Google Scholar 

  27. Kedia G, Ückert S, Kedia M, Truss MC, Chigogidze T, Jonas U, Managadze L (2006) In vitro effects of drugs interfering with the cAMP- and cGMP-pathway on the tension induced by endothelin-1 of isolated human prostate tissue. Georgian Med News 131:7–13

    Google Scholar 

  28. Ückert S, Sormes M, Kedia G, Gratzke C, Stief CG, Scheller F, Jonas U (2006) Effects of PDE inhibitors on the tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostate tissue. Urologe 45(Suppl 1):25–26 (abstract)

    Google Scholar 

  29. Kedia G, Sormes M, Ückert S, Scheller F, Jonas U (2007) Contraction-relaxation studies on isolated human prostate tissue: the role of endothelin 1, phosphodiesterase inhibitors and cyclic nucleotides. Eur Urol 6(Suppl 2):34 (Abstract)

    Google Scholar 

  30. Stief CG, Ückert S, Becker AJ, Harringer W, Truss MC, Forssmann WG, Jonas U (2000) Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. Urology 55:146–150

    Article  PubMed  CAS  Google Scholar 

  31. Friebe A, Müllershausen F, Smolenski A, Walter U, Schultz G, Koesling D (1998) YC-1 potentiates nitric oxide- and carbon monoxide-induced GMP effects in human platelets. Mol Pharmacol 54:962–967

    PubMed  CAS  Google Scholar 

  32. Müllershausen F, Russwurm M, Friebe A, Koesling D (2004) Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41–2272. Circulation 109:1711–1713

    Article  PubMed  Google Scholar 

  33. Klotz T, Mathers MJ, Bloch W, Nayal W, Engelmann U (1999) Nitric oxide based influence of nitrates on micturition in patients with benign prostatic hyperplasia. Int Urol Nephrol 31:335–341

    Article  PubMed  CAS  Google Scholar 

  34. Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, Hanbury DC (2002) Sildenafil influences lower urinary tract symptoms. BJU Int 90:836–839

    Article  PubMed  CAS  Google Scholar 

  35. Mulhall JP, Guhring P, Parker M, Hopps C (2006) Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med 3:662–667

    Article  PubMed  CAS  Google Scholar 

  36. Ying J, Yao D, Jiang Y, Ren X, Xu M (2004) The positive effect of sildenafil on LUTS from BPH while treating ED. Zhonghua Nan Ke Xue 10:681–683

    PubMed  Google Scholar 

  37. Kaplan SA, Gonzalez RR, Te AE (2007) Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 51:1717–1723

    Article  PubMed  CAS  Google Scholar 

  38. McVary KT, Monnig W, Camps JL, Young JM, Tseng LJ, van den Ende G (2007) 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

    Article  PubMed  CAS  Google Scholar 

  39. McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM, Esler A, Sides GD, Denes BS (2007) Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 177:1401–1407

    Article  PubMed  CAS  Google Scholar 

  40. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E (2008) 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

    Article  PubMed  CAS  Google Scholar 

  41. Tinel H, Stelte-Ludwig B, Hütter J, Sandner P (2006) Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms. BJU Int 98:1259–1263

    Article  PubMed  CAS  Google Scholar 

  42. Filippi S, Morelli A, Sandner P, Fibbi B, Mancina R, Marini M, Gacci M, Vignozzi L, Vanneli GB, Carini M, Forti G, Maggi M (2007) Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 148:1019–1029

    Article  PubMed  CAS  Google Scholar 

  43. Yono M, Yamamoto Y, Yoshida M, Ueda S, Latifpour J (2007) Effects of doxazosin on blood flow and mRNA expression of nitric oxide synthase in the spontaneously hypertensive rat genitourinary tract. Life Sci 81:218–222

    Article  PubMed  CAS  Google Scholar 

  44. Pinggera GM, Schuster A, Frauscher F, Bartsch G, Strasser H (2004) Sildenafil citrate causes a 3-fold increase in periurethral prostatic blood flow. J Urol 171(Suppl 4):355 (abstract)

    Google Scholar 

  45. Guh JH, Hwang TL, Ko FN, Chueh SC, Lai MK, Teng CM (1998) Antiproliferative effect in human prostatic smooth muscle cells by nitric oxide donor. Mol Pharmacol 53:467–474

    PubMed  CAS  Google Scholar 

  46. Adolfsson PI, Ahlstrand C, Varenhorst E, Svensson SP (2002) Lysophosphatidic acid stimulates proliferation of cultured muscle cells from human BPH tissue: sildenafil and papaverine generate inhibition. Prostate 51:50–58

    Article  PubMed  CAS  Google Scholar 

  47. Deng CH, Chen HR, Qiu SP, Liu JZ, Zheng KL, Mei H (2004) Effect of nitric oxide donor and alpha1-receptor antagonist on proliferation/apoptosis of hyperplastic prostatic stromal cells in vitro. Zhonghua Wai Ke Za Zhi 42:201–204

    PubMed  Google Scholar 

  48. Reynard JM, Yang Q, Donovan JL, Peters TJ, Schäfer W, de la Rosette JJ, Dabhoiwala NF, Osawa D, Lim AT, Abrams P (1998) The ICS-BPH study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. Br J Urol 82:619–623

    PubMed  CAS  Google Scholar 

  49. Oelke M, Baard J, Wijkstra H, de la Rosette JJ, Jonas U, Höfner K (2008) Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. Eur Urol (Epub ahead of print)

  50. Shapiro E, Hartanto V, Lepor H (1992) The response to alpha-blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate 21:297–307

    Article  PubMed  CAS  Google Scholar 

  51. Ückert S, Mayer ME, Stief CG, Jonas U (2007) The future of the oral pharmacotherapy of male erectile dysfunction - things to come. Expert Opin Emerg Drugs 12:219–228

    Article  PubMed  Google Scholar 

  52. de Nucci G, Lorenzetti R, Okuyama CE, Baracat JS, Donato JL, Antunes E, Teixeira CE (2007) Pharmacological characterization of the novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. Urology 70(Suppl 3A):105 (abstract)

    Google Scholar 

Download references

Conflict of interest statement

There is no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George T. Kedia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kedia, G.T., Ückert, S., Jonas, U. et al. The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms. World J Urol 26, 603–609 (2008). https://doi.org/10.1007/s00345-008-0303-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-008-0303-y

Keywords

Navigation