Skip to main content
SpringerLink
Log in

Cyclic Nucleotide Metabolism Including Nitric Oxide and Phosphodiesterase-Related Targets in the Lower Urinary Tract

  • Chapter
  • First Online:
Urinary Tract

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 2011))

Abstract

The clinical data on the use of the orally active phosphodiesterase (PDE) type 5 inhibitors sildenafil (VIAGRA™), vardenafil (LEVITRA™), and tadalafil (CIALIS™) for the treatment of male erectile dysfunction have boosted research activities on the physiology and pharmacology of the organs of the lower urinary tract (LUT). This includes both intracellular signal transduction in the prostate, urinary bladder (detrusor), and urethra, as well as central brain and spinal cord pathways controlling the function of the LUT. Such efforts provided the basis for the development of new therapeutic modalities into themanagement of dysfunctions/ syndromes of the LUT, some of which are already offered to the patients. The pharmacological treatment of the overactive bladder and the so-called benign prostatic syndrome, including LUT symptomatology and bladder outlet obstruction secondary to benign prostatic enlargement, has primarily focused on selective, orally available drugs acting by influencing intracellular regulatory mechanisms. These agents are regarded efficacious, have a fast onset of drug action in the target tissue and an improved effect-to-side-effect ratio. Better understanding of the functional significance of proteins related to cyclic nucleotide-dependent pathways, such as nitric oxide synthase, cytosolic and membrane-bound guanylyl cyclases, PDE isoenzymes and cyclic AMP- and cyclic GMP-binding protein kinases, the relative distribution in tissues of the LUT, and the consequences for urogenital function, seems to be of particular interest in order to identify new or more selective pharmacological approaches to manage disorders of the LUT. The present review focuses on cyclic nucleotide-related targets involved in the control of the function of the bladder, prostate, and urethra and the significance of those proteins in the process of evolving new pharmacological options for the treatment of LUT symptoms secondary to benign prostatic hyperplasia as well as dysfunctions of the storage and voiding capability of the urinary bladder.

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

  • Alm P, Larsson B, Ekblad E, Sundler F, Andersson KE (1993) 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

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Andersson KE (1993) Pharmacology of lower urinary tract smooth muscle and penile erectile tissues. Pharmacol Rev 45:253–308

    Google Scholar 

  • Andersson KE, Persson K (1993) The L-arginine/nitric oxide pathway and nonadrenergic-noncholinergic relaxation of the lower urinary tract. Gen Pharmacol 24:833–839

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Bennett BC, Kruse MN, Roppolo JR, Flood HD, Fraser M, de Groat WC (1995) Neural control of urethral outlet activity in vivo: role of nitric oxide. J Urol 153:2004–2009

    Article  CAS  PubMed  Google Scholar 

  • Bischoff E, Schramm M, Straub A, Feurer A, Stasch JP (2003) BAY 41-2272: a stimulator of soluble guanylyl cyclase induces nitric oxide dependent penile erection. Urology 61:464–467

    Article  CAS  PubMed  Google Scholar 

  • Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L (2010) Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology 75:1452–1458

    Article  PubMed  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  CAS  PubMed  Google Scholar 

  • Denninger JW, Marletta MA (1999) Guanylate cyclase and the NO/cGMP signalling pathway. Biochim Biophys Acta 1411:334–350

    Article  CAS  PubMed  Google Scholar 

  • Ehren I, Iversen H, Jansson O, Adolfsson J, Wiklund NP (1994) Localization of nitric oxide synthase activity in the human lower urinary tract and its correlation with neuroeffector responses. Urology 44:683–687

    Article  CAS  PubMed  Google Scholar 

  • Elesber AA, Solomon H, Lennon RJ, Mathew V, Prasad A, Pumper G, Nelson RE, McConnell JP, Lerman LO, Lerman A (2006) Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur Heart J 27:824–831

    Article  CAS  PubMed  Google Scholar 

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

    Article  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  CAS  PubMed  Google Scholar 

  • Feil R, Gappa N, Rutz M, Schlossmann J, Rose CR, Konnerth A, Brummer S, Kuhbandner S, Hofman F (2002) Functional reconstitution of vascular smooth muscle cells with cGMP-dependent protein kinase I isoforms. Circ Res 90:1080–1086

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Ganz P (2005) Erectile dysfunction: pathophysiologic mechanisms pointing to underlying cardiovascular disease. Am J Cardiol 96:8M–12M

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  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 

  • Guven EO, Balbay MD, Mete K, Serefoglu EC (2009) Uroflowmetric assessment of acute effects of sildenafil on the voiding of men with erectile dysfunction and symptomatic benign prostatic hyperplasia. Int Urol Nephrol 41:287–92

    Article  PubMed  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Hedlund P, Aszodi A, Pfeifer A, Alm P, Hofman F, Ahmad M, Fassler R, Andersson KE (2000) Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci U S A 97:2349–2354

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ho KM, McMurray G, Brading AF, Noble JG, Ny L, Andersson KE (1998) Nitric oxide synthase in the heterogeneous population of intramural striated muscle fibres of the human membranous urethral sphincter. J Urol 159:1091–1096

    Article  CAS  PubMed  Google Scholar 

  • Hobbs AJ (2002) Soluble guanylate cyclase: an old therapeutic target re-visited. Br J Pharmacol 136:637–640

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Kedia GT, Ückert S, Steffenhagen V, Sonnenberg JE, Kuczyk MA (2009) Expression von Phosphodiesterase (PDE)-Isoenzymen in der humanen Urethra – Eine molekularbiologische Studie. Abstract presented at the 3. Nordkongress Urologie, Braunschweig, Germany, 14–16 May 2009

    Google Scholar 

  • Komalavilas P, Lincoln TM (1994) Phosphorylation of the inositol-1, 4, 5-trisphosphate receptor by cyclic GMP-dependent protein kinase. J Biol Chem 269:8701–8107

    CAS  PubMed  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 

  • Lee YC, Martin E, Murad F (2000) Human recombinant soluble guanylyl cyclase: expression, purification, and regulation. Proc Natl Acad Sci U S A 97:10763–10768

    Article  CAS  PubMed  Google Scholar 

  • Lincoln TM, Thompson M, Cornwell TL (1988) Purification and characterization of two forms of cyclic GMP-dependent protein kinase from bovine aorta. J Biol Chem 263:17632–17637

    CAS  PubMed  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  CAS  PubMed  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

    CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Miller LN, Nakane M, Hsieh GC, Chang R, Kolasa T, Moreland RB, Brioni JD (2003) A-350619: a novel activator of soluble guanylyl cyclase. Life Sci 72:1015–1025

    Article  CAS  PubMed  Google Scholar 

  • Moreland RB, Hsieh GC, Nakane M, Miller LN, Chang R, Kolasa T, Sullivan J, Brioni JD (2002) Novel soluble guanylate cyclase activators A-344905 and A-305619 activate sGC in vitro and facilitate penile erection in rats. J Urol 167(suppl 4):938 (Abstract)

    Google Scholar 

  • Mumtaz FH, Sullivan ME, Thompson CS, Dashwood MR, Naseem KM, Bruckdorfer KR, Mikhailidis DP, Morgan RJ (1999) Alterations in the nitric oxide synthase binding sites and non-adrenergic, non-cholinergic mediated smooth muscle relaxation in the diabetic rabbit bladder outlet: possible relevance to the pathogenesis of diabetic cystopathy. J Urol 162:558–566

    Article  CAS  PubMed  Google Scholar 

  • Persson K, Pandita RK, Aszodi A, Ahmad M, Pfeifer A, Fassler R, Andersson KE (2000) 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

    CAS  PubMed  Google Scholar 

  • Reitz A, Bretscher S, Knapp PA, Muntener M, Wefer B, Schurch B (2004) The effect of nitric oxide on the resting tone and the contractile behaviour of the external urethral sphincter: a functional urodynamic study in healthy humans. Eur Urol 45:367–373

    Article  CAS  PubMed  Google Scholar 

  • Riffaud JP, Bernarbe J, Giuliano F, Jones R, Jeremy J (2001) Pharmacological profile of sildenafil nitrate (NCX 911) in various models of penile erection. Inflamm Res 50(suppl 3):84 (Abstract)

    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 

  • Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, Viktrup L (2009) Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int 105:502–507

    Article  PubMed  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

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Sawada N, Itoh H, Yamashita J, Doi K, Inoue M, Masatsugu K, Fukunaga Y, Sakaguchi S, Sone M, Yamahara K, Yurugi T, Nakao K (2001) cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun 280:798–805

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Stasch JP, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Minuth T, Perzborn E, Schramm M, Straub A (2002) Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol 135:333–343

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Straub A, Stasch JP, Alonso-Alija C, Benet-Buchholz I, Ducke B, Feurer A, Minuth T, Perzborn E, Schramm M, Straub A (2001) NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 11:781–784

    Article  CAS  PubMed  Google Scholar 

  • Surks HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M, Lincoln TM, Mendelsohn ME (1999) Regulation of myosin phosphatase by a specific interaction with cGMP-dependent protein kinase Iα. Science 286:1583–1587

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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  CAS  PubMed  Google Scholar 

  • Werkström V, Svensson A, Andersson KE, Hedlund P (2006) Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects. BJU Int 98:414–423

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, Hannover, 30623, Germany

    Stefan Ückert & Markus A. Kuczyk

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

    Stefan Ückert

Authors
  1. Stefan Ückert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus A. Kuczyk
    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. Wake Forest University, Medical Center Blvd., Winston-Salem, 27157-1088, North Carolina, USA

    Karl-Erik Andersson

  2. Academic Medical Center, Dept. Pharmacology & Pharmacotherapy, University of Amsterdam, Meibergdreef 15, Amsterdam, 1105 AZ, Netherlands

    Martin C. Michel

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ückert, S., Kuczyk, M.A. (2011). Cyclic Nucleotide Metabolism Including Nitric Oxide and Phosphodiesterase-Related Targets in the Lower Urinary Tract. In: Andersson, KE., Michel, M. (eds) Urinary Tract. Handbook of Experimental Pharmacology, vol 2011. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16499-6_23

Download citation

Publish with us

Policies and ethics

Search

Navigation