Skip to main content
SpringerLink
Log in

Treatment of Erectile Dysfunction and Lower Urinary Tract Symptoms by Phosphodiesterase Inhibitors

  • Chapter
  • First Online:
Phosphodiesterases as Drug Targets

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 204))

Abstract

To date, it is widely accepted that several disorders of the male and female urogenital tract, such as erectile dysfunction, bladder overactivity, urinary stone disease, the benign prostatic syndrome, as well as symptoms of female sexual arousal and orgasmic dysfunctions, can be therapeutically approached by influencing the function of the smooth musculature of the respective organs. To achieve a pronounced drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. Selective intervention in intracellular pathways regulating smooth muscle tone has become the most promising strategy to modulate tissue and organ function. Since the concept of taking a pill to relieve symptoms of lower urinary tract dysfunction is now widely accepted following the successes of phosphodiesterase 5 (PDE5) inhibitor treatment of erectile dysfunction, the treatment of urological diseases has focused on orally available drugs acting via influencing intracellular signaling pathways, thereby combining a high response rate with the advantage of an on-demand intake. Specifically, the use of isoenzyme-selective PDE inhibitors offers great opportunities in the medical treatment of various genitourinary diseases. These agents are regarded to be safe and to be efficacious, i.e., having a fast onset of drug action and an improved effect-to-side-effect ratio. As experience with this class of compounds and their use in urology is rapidly growing, basic and clinical research in this field will most likely expand the pharmacological armamentarium of innovative treatment options in the next few years. The purpose of this review is to summarize current, as well as potential, upcoming indications for the use of PDE inhibitors in the pharmacotherapy of male erectile dysfunction and lower urinary tract symptoms.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andersen JT, Ekman P, Wolf H, Beisland HO, Johansson JE, Kontturi M, Lehtonen T, Tveter K (1995) Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology 46:631–637

    Article  PubMed  CAS  Google Scholar 

  • Andersson KE (2008) How many drugs for LUTS due to BPH are too many? J Urol 180:811–812

    Article  PubMed  CAS  Google Scholar 

  • Andersson KE, Chapple C, Wein A (2001) The basis for drug treament of the overactive bladder. World J Urol 19:294–298

    Article  PubMed  CAS  Google Scholar 

  • Antoni FA (2000) Molecular diversity of cAMP signaling. Front Neuroendocrinol 21:103–132

    Article  PubMed  CAS  Google Scholar 

  • Becker AJ, Stief CG, Meyer M, Truss MC, Forssmann WG, Jonas U (1998) The effect of the specific phosphodiesterase 4 inhibitor rolipram on the ureteral peristalsis in vitro and in vivo. J Urol 160:920–925

    Article  PubMed  CAS  Google Scholar 

  • Cahn D, Melman A, Valcic M, Christ GJ (1997) Forskolin: a promising new adjunct to intracavernous pharmacotherapy. J Urol 155:1789–1794

    Article  Google Scholar 

  • Chiricos TN, Sanford E (1996) Cost consequences of surveillance, medical management or surgery for benign prostatic hyperplasia. J Urol 155:1311–1316

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Eardly I, Cartledge J (2002) Tadalafil (CIALIS) for men with erectile dysfunction. Int J Clin Pract 56:300–304

    Google Scholar 

  • Emmick JT, Stuewe SR, Mitchell M (2002) Overview of the cardiovascular effects of tadalafil. Eur Heart J 4(suppl H):H32–H47

    CAS  Google Scholar 

  • Essayan DM (2001) Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 108:671–680

    Article  PubMed  CAS  Google Scholar 

  • Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S, Hetman J, Beavo JA, Philips SC (2000) Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci USA 97:3702–3707

    Article  PubMed  CAS  Google Scholar 

  • Fink HA, McDonald R, Rutks IR, Nelson DB, Wilt TJ (2002) Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 162:1349–1360

    Article  PubMed  CAS  Google Scholar 

  • Fisher AD, Smith JF, Pillar JS, St Denis S, Cheng JB (1998a) Isolation and characterization of PDE8A, a novel cAMP-specific phosphodiesterase. Biochem Biophys Res Commun 246:570–577

    Article  PubMed  CAS  Google Scholar 

  • Fisher AD, Smith JF, Pillar JS, St Denis S, Cheng JB (1998b) Isolation and characterization of PDE9A, a novel cGMP-specific phosphodiesterase. J Biol Chem 273:15559–15564

    Article  PubMed  CAS  Google Scholar 

  • Gacci M, del Popolo G, Macchiarella A, Celso M, Vittori G, Lapini A, Serni S, Sandner P, Maggi M, Carini M (2007) Vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study. J Urol 178:2040–2043

    Article  PubMed  CAS  Google Scholar 

  • Glina S, Toscano I, Gomatzky C, de Goes PM, Junior AN, Claro JF, Pagani E (2009) Efficacy and tolerability of lodenafil carbonate for oral therapy in erectile dysfunction: a phase II clinical trial. J Sex Med 6:553–557

    Article  PubMed  CAS  Google Scholar 

  • Gratzke C, Ückert S, Kedia G, Reich O, Schlenker B, Seitz M, Becker AJ, Stief CG (2007) In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. Urol Res 35:49–54

    Article  PubMed  CAS  Google Scholar 

  • Greco EA, Spera G, Aversa A (2006) Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic rationale and clinical evidences. Eur Urol 50:940–947

    Article  PubMed  CAS  Google Scholar 

  • Guay D, Hamel P, Blouin M, Brideau C, Chan CC, Chauret N, Ducharme Y, Huang Z, Girard M, Jones TR, Laliberte F, Masson P, McAuliffe M, Piechuta H, Silva J, Young RN, Girard Y (2002) Discovery of L-791.943: a potent, selective, non-emetic and orally active phosphodiesterase 4 inhibitor. Bioorg Med Chem Lett 12:1457–1461

    Article  PubMed  CAS  Google Scholar 

  • Guess HA (1995) Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 22:247–261

    PubMed  CAS  Google Scholar 

  • Gülcer C, Tüzel E, Dogantekin E, Kiziltepe G (2008) Does sildenafil affect uroflowmetry values in men with lower urinary tract symptoms suggestive of benign prostatic enlargement? Urol Int 80:181–185

    Article  Google Scholar 

  • Gur S, Sikka SC, Hellstrom WJ (2008) Novel phosphodiesterase 5 (PDE5) inhibitors in the alleviation of erectile dysfunction due to diabetes and ageing-induced oxidative stress. Expert Opin Investig Drugs 17:855–864

    Article  PubMed  CAS  Google Scholar 

  • Gutierrez P, Hernandez P, Mas M (2005) Combining programmed intracavernous PGE1 injections and sildenafil on demand to salvage sildenafil non-responders. Int J Impot Res 17:354–358

    Article  PubMed  CAS  Google Scholar 

  • Han P, Zhu X, Michaeli T (1997) Alternative splicing of the high affinity cAMP-specific phosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. J Biol Chem 272:16152–16157

    Article  PubMed  CAS  Google Scholar 

  • Hatzimouratidis K, Hatzichristou DG (2008) Looking to the future for erectile dysfunction therapies. Drugs 68:231–250

    Article  PubMed  CAS  Google Scholar 

  • Heaton JP, Morales A, Owen J (1990) Topical glyceryltrinitrate causes measurable penile arterial dilatation in impotent men. J Urol 143:729–731

    PubMed  CAS  Google Scholar 

  • Hieble JR, Ruffolo RR Jr (1996) The use of alpha-adrenoceptor antagonists in the pharmacological management of benign prostatic hyperplasia: an overview. Pharmacol Res 33:145–160

    Article  PubMed  CAS  Google Scholar 

  • Holmquist F, Stief CG, Jonas U, Andersson KE (1991) Effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine on the erectile response to cavernous nerve stimulation in the rabbit. Acta Physiol Scand 143:299–304

    Article  PubMed  CAS  Google Scholar 

  • Jacobsen SJ, Guess HA, Panser L, Girman CJ, Chute CG, Oesterling JE, Lieber MM (1993) A population-based study of health care-seeking behaviour for treatment of urinary symptoms. Arch Fam Med 2:729–735

    Article  PubMed  CAS  Google Scholar 

  • Kalsi JS, Kell PD (2004) Update on the oral treatments for male erectile dysfunction. J Eur Acad Dermatol Venereol 18:267–274

    Article  PubMed  CAS  Google Scholar 

  • Kang KK, Yu JY, Yoo M, Kwon JW (2005) The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction. Int J Impot Res 17:409–416

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Kühn R, Ückert S, Stief CG, Truss MC, Lietz B, Bischoff E, Schramm M, Jonas U (2000) Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide dependent pathways. Urol Res 28:110–115

    Article  PubMed  Google Scholar 

  • Küthe A, Mägert HJ, Ückert S, Forssmann WG, Stief CG, Jonas U (2000) Gene expression of the phosphodiesterases 3A and 5A in human corpus cavernosum penis. Eur Urol 38:108–114

    Article  PubMed  Google Scholar 

  • Küthe A, Wiedenroth A, Mägert HJ, Ückert S, Forssmann WG, Stief CG, Jonas U (2001) Expression of different phosphodiesterase genes in human cavernous smooth muscle. J Urol 165:280–283

    Article  PubMed  Google Scholar 

  • Liguori G, Trombetta C, de Giorgi G, Pomara G, Maio G, Vecchio D, Ocello G, Ollandini G, Bucci S, Belgrano E (2009) Efficacy and safety of combined oral therapy with tadalafil and alfuzosin: an integrated approach to the management of patients with lower urinary tract symptoms and erectile dysfunction. Preliminary report. J Sex Med 6:544–552

    Article  PubMed  CAS  Google Scholar 

  • Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA (1999) Isolation and characterization of PDE10A, a novel human 3’.5’-cyclic nucleotide phosphodiesterase. Gene 234:109–117

    Article  PubMed  CAS  Google Scholar 

  • Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52:375–414

    PubMed  CAS  Google Scholar 

  • Maurice DH, Palmer D, Tilley DG, Dunkerley HA, Netherton SJ, Raymond DR, Elbatany HS, Jimmo SL (2003) Cyclic nucleotide phosphodiesterase activity, expression, and targeting cells in the cardiovascular system. Mol Pharmacol 64:533–546

    Article  PubMed  CAS  Google Scholar 

  • Mazzu A, Nicholls A, Zinny M (2001) Vardenafil: a new highly selective PDE5 inhibitor, interacts minimally with nitroglycerin in healthy middle-aged subjects. Int J Impot Res 13(suppl 5):S64 (Abstract)

    Google Scholar 

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

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

    Article  PubMed  CAS  Google Scholar 

  • Michaeli T, Bloom TJ, Martins T, Loughney K, Ferguson K, Riggs M, Rodgers L, Beavo JA, Wigler M (1994) Isolation and characterization of a previously undetected human cAMP phosphodiesterase by complementation of cAMP phosphodiesterase deficient Saccharomyces cerevisiae. J Biol Chem 268:12925–12932

    Google Scholar 

  • Oger S, Behr-Roussel D, Gorny D, Denys P, Lebret T, Alexandre L, Giuliano F (2007) Relaxation of phasic contractile activity of human detrusor strips by cyclic nucleotide phosphodiesterase type 4 inhibition. Eur Urol 51:772–780

    Article  PubMed  CAS  Google Scholar 

  • Ottensen B, Wagner G, Virag R, Fahrenkrug J (1984) Penile erection: possible role for vasoactive intestinal polypeptide as a neurotransmitter. Br J Med 288:9–11

    Article  Google Scholar 

  • Porst H (1996) The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol 155:802–815

    Article  PubMed  CAS  Google Scholar 

  • Rajasekaran M, Sikka S, Hellstrom W, Doherty P (1998) Evidence for the presence of the type 4 phosphodiesterase in isolated human cavernosal smooth muscle cells. Int J Impot Res 10(suppl 3):S55 (Abstract)

    Google Scholar 

  • Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ (1992) Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to non-adrenergic, non-cholinergic neurotransmission. N Engl J Med 326:90–94

    Article  PubMed  CAS  Google Scholar 

  • Roehrborn CG, Marks LS, Fenter T, Freedman S, Tuttle J, Gittleman M, Morril B, Wolford ET (2004) Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 63:709–715

    Article  PubMed  Google Scholar 

  • Rybulkin SD, Yan C, Bornfeld KE, Beavo JA (2003) Cyclic GMP phosphodiesterase and smooth muscle function. Circ Res 93:280–291

    Article  Google Scholar 

  • Saighi D, Zerbib M, Thiounn N, Flam T, Conquy S, Jacob L, dall'Ava-Santucci J, Debré B, Dinh-Xuan AT (2000) In vitro study of the modulation of human ureteral tonus by nitric oxide and zaprinast, a phosphodiesterase inhibitor. Prog Urol 10:1161–1168

    PubMed  CAS  Google Scholar 

  • 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 

  • Silver PJ, Dundore RL, Bode DC, de Garavilla L, Buchholz RA, van Aller G, Hamel LT, Bacon E, Singh B, Lesher GY (1997) Cyclic GMP potentiation by WIN 58237, a novel cyclic nucleotide phosphodiesterase inhibitor. J Pharmacol Exp Ther 271:1143–1149

    Google Scholar 

  • Smet PJ, Edyvane KA, Jonasvicius J, Marshall VR (1994) Colocalisation of nitric oxide synthase with vasoactive intestinal peptide, neuropeptide Y and thyrosine hydroxylase in nerves supplying the human ureter. J Urol 152:1292–1296

    PubMed  CAS  Google Scholar 

  • Sommer F, Engelmann U (2004) Future options for combination therapy in the management of erectile dysfunction in older men. Drugs Aging 21:555–564

    Article  PubMed  CAS  Google Scholar 

  • Stief C, Porst H, Saenz de Tejada I, Ulbrich E, Beneke M, Vardenafil Study Group (2004) Sustained efficacy and tolerability with vardenafil over two years of treatment in men with erectile dysfunction. Int J Clin Pract 58:230–239

    Article  PubMed  CAS  Google Scholar 

  • Stief CG, Ückert S, Truss MC, Becker AJ, Machtens S, Jonas U (1996) A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro. Urol Res 24:333–337

    Article  PubMed  CAS  Google Scholar 

  • Stief CG, Ückert S, Becker AJ, Truss MC, Jonas U (1998) Effects of specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J Urol 159:1390–1393

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Taher A, Schulz-Knappe P, Meyer M, Truss MC, Forssmann WG, Stief CG, Jonas U (1994) Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol 12:286–291

    Article  PubMed  CAS  Google Scholar 

  • Taher A, Meyer M, Stief CG, Jonas U, Forssmann WG (1997) Cyclic nucleotide phosphodiesterase isoenzymes in human cavernous smooth muscle. World J Urol 15:32–35

    Article  PubMed  CAS  Google Scholar 

  • Thadani U, Mazzu A (2002) Exercise-induced ischemia was not adversely affected by vardenafil during exercise stress test in men with coronary artery disease. Eur Urol 1(suppl 1):151 (Abstract)

    Google Scholar 

  • Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, de Nucci G (2008) Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor, lodenafil carbonate, on human and rabbit corpus cavernosum. Eur J Pharmacol 591:189–195

    Article  PubMed  CAS  Google Scholar 

  • Truss MC, Becker AJ, Djamillian MH, Stief CG, Jonas U (1994) Role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the diagnosis and treatment of erectile dysfunction. Urology 44:553–556

    Article  PubMed  CAS  Google Scholar 

  • Truss MC, Ückert S, Stief CG, Kuczyk MA, Jonas U (1996a) Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle: I. Identification and characterization. Urol Res 24:123–128

    Article  PubMed  CAS  Google Scholar 

  • Truss MC, Ückert S, Stief CG, Kuczyk MA, Jonas U (1996b) 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

    Article  PubMed  CAS  Google Scholar 

  • Truss MC, Stief CG, Ückert S, Becker AJ, Wefer J, Schultheiss D, Jonas U (2001) Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol 19:344–350

    Article  PubMed  CAS  Google Scholar 

  • Ückert S, Sandner P, Sigl K, Ulbrich E, Stief CG, Kuczyk MA (2009) Is there a role of the phosphodiesterase type 5 (PDE5) in the control of detrusor smooth muscle? A functional and molecular biology study. J Urol 181(suppl 4):152 (Abstract)

    Article  Google Scholar 

  • Ückert S, Küthe A, Stief CG, Jonas U (2001a) Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. World J Urol 19:14–22

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Ückert S, Hedlund P, Waldkirch E, Sohn M, Jonas U, Andersson KE, Stief CG (2004) Interactions between cGMP- and cAMP-pathways are involved in the regulation of penile smooth muscle tone. World J Urol 22:261–266

    Article  PubMed  Google Scholar 

  • 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 

Download references

Author information

Authors and Affiliations

  1. Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, 30625, Hannover, Germany

    Stefan Ückert

  2. Urological Research Unit, Institute for Biochemical Research and Analysis, Medical Park Business Area, Hannover, Germany

    Stefan Ückert

  3. Faculty of Medicine, Department of Urology, Ludwig-Maximilians-University, University Hospital Grosshadern, Munich, Germany

    Christian G. Stief

Authors
  1. Stefan Ückert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian G. Stief
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Ückert .

Editor information

Editors and Affiliations

  1. School of Medicine, Dept. Molecular Physiology & Biophysics, Vanderbilt University, Light Hall 702, Nashville, 37232-0615, Tennessee, USA

    Sharron H. Francis

  2. HSW 1656, Center for Reproductive Sciences, Parnassus Avenue 513, San Francisco, 94143-0556, California, USA

    Marco Conti

  3. Wolfson Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom

    Miles D. Houslay

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ückert, S., Stief, C.G. (2011). Treatment of Erectile Dysfunction and Lower Urinary Tract Symptoms by Phosphodiesterase Inhibitors. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_13

Download citation

Publish with us

Policies and ethics

Search

Navigation