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Erectile Dysfunction and Lower Urinary Tract

  • Chapter
cGMP: Generators, Effectors and Therapeutic Implications

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 191))

Abstract

Abstract During the last decades it turned out that the NO/cGMP signaling cascade is one of the most prominent regulators of a variety of physiological and pathophysiological processes in a broad range of mammalian tissues. Thus cGMP is a key second messenger and targeting this pathway by increasing intracellular cGMP levels is a very successful approach in pharmacology as shown for nitrates, PDE5 inhibitors and more recently for stimulators of the guanylate cyclase. Besides the beneficial effects of cGMP elevation in cardiac, vascular, pulmonary, renal or liver disorders the launch of PDE5 inhibitors for the treatment of erectile dysfunction 10 years ago, has directed a lot of attention to the NO/cGMP signaling in the lower urinary tract. Triggered by the use of PDE5 inhibitors in ED it turned out that cGMP is a common regulatory mechanism for lower urinary tract function also beyond ED. In recent years intense research and development efforts were undertaken to elucidate the role of the NO/cGMP and to fully exploit the therapeutic implications of cGMP elevation in urological disorders in ED and beyond. Therefore we have summarized the effects of cGMP elevation for treatment of erectile dysfunction in males and in females. We have also reviewed the recent pre-clinical and clinical lines of evidence for treatment options of benign prostatic hyperplasia and lower urinary tract symptoms in male patients and overactive bladder and urinary incontinence in female patients. In addition we also touch more speculative concepts using cGMP elevating drugs for the treatment of premature ejaculation, peyornies disease and stone disease.

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References

  • Abrams P (1994) New words for old: lower urinary tract symptoms for prostatism. Br Med J 308:929–930

    CAS  Google Scholar 

  • Abrams P, Cardozo L, Fall M, et al (2002) The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the internation continence society. Neurourol Urodyn 21:167–178

    PubMed  Google Scholar 

  • Adolfsson PI, Ahlstrand C, Varenhorst E, et al (2002) Lysophosphatidic acid stimulates prolifera tion of cultured smooth muscle cells from human BPH tissue: sildenafil and papaverin generate inhibition. Prostate 51(1):50–58

    PubMed  CAS  Google Scholar 

  • Althof SE (2006) Prevalence, characteristics and implication of premature ejaculation/rapid ejacu lation. J Urol 175:842–848

    PubMed  Google Scholar 

  • Althof SE, Rosen RC, DeRogatis L, et al (2005) Outcome measurement in female sexual dysfunc tion clinical trials: review and recommendations. J Sex Marital Ther 31(2):153–166

    PubMed  Google Scholar 

  • Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology andpPatho-physiology. Physiol Rev 84:935–986

    PubMed  CAS  Google Scholar 

  • Aschka C, Himmel W, Ittner E, et al (2001) Sexual problems of male patients in family practice. J Fam Pract 50:773–778

    PubMed  CAS  Google Scholar 

  • Ayta IA, McKinlay JB, Krane RJ (1999) The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 84:50–56

    PubMed  CAS  Google Scholar 

  • Azadzoi KM, Babayan RK, Kozlowski R, et al (2003) Chronic ischemia increases prostatic smooth muscle contraction in the rabbit. J Urol 170(2):659–663

    PubMed  Google Scholar 

  • Baracat JS, Teixeira CE, Okuyama CE, et al (2003) Relaxing effects induced by the soluble guany lyl cyclase stimulator BAY 41–2272 in human and rabbit corpus cavernosum. Eur J Pharmacol 477(2):163–169

    PubMed  CAS  Google Scholar 

  • Basson R, Brotto LA (2003) Sexual psychophysiology and effects of sildenafil citrate in oestro genised women with acquired genital arousal disorder and impaired orgasm: a randomized controlled trial. BJOG 110(11):1014–1024

    PubMed  CAS  Google Scholar 

  • Basson R, McInnes R, Smith MD, et al (2002) Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J Womens Health Gend Based Med 11(4):367–377

    PubMed  Google Scholar 

  • Beamon C, Salkini M, Mazur C, et al (2007) The effect of sildenafil citrate on bladder outlet obstruction in a mouse model. J Urol 177(suppl):140

    Google Scholar 

  • Becker AJ, Stief CG, Meyer M, et al (1998) The effect of the specific phosphodiesterase-IV-inhibitor rolipram on the ureteral peristalsis of the rabbit in vitro and in vivo. J Urol 160(3): 920–925

    PubMed  CAS  Google Scholar 

  • Behr-Roussel D, Oger S, Tinel H, et al (2008) PDE5 gene expression and relaxant effects of var denafil in male and female human and rat detrusor muscle. Eur Urol 7(3):263

    Google Scholar 

  • Berman JR, Bassuk J (2002) Physiology and pathophysiology of female sexual function and dys function. World J Urol 20(2):111–118

    PubMed  Google Scholar 

  • Berman JR, Berman LA, Toler SM, et al (2003) Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J Urol 170:2333–2338

    PubMed  CAS  Google Scholar 

  • Bialy M, Beck J, Abramczyk P, Treszebski A, et al (1996) Sexual behaviour in male rats after nitric oxide synthase inhibition. Physiol Behav 60:139–143

    PubMed  CAS  Google Scholar 

  • Bischoff E, Schneider K (2001) A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection. Int J Impot Res 13:230–235

    PubMed  CAS  Google Scholar 

  • Bischoff E, Stasch JP (2004) Effects of the sGC stimulator BAY 41-2272 are not mediated by phosphodiesterase 5 inhibition. Circulation 110(12):320–321

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Bivalacqua TJ, Usta MF, Champion HC, et al (2004) Effect of combination endothelial nitric ox ide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 16(1):21–29

    PubMed  CAS  Google Scholar 

  • Boolell M, Allen MJ, Ballard SA, et al (1996) Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 8:47–52

    PubMed  CAS  Google Scholar 

  • Braun M, Wassmer G, Klotz T, et al (2000) Epidemiology of erectile dysfunction: results of the ‘Cologne Male Survey’. Int J Impot Res 12:305–311

    PubMed  CAS  Google Scholar 

  • Burnett AL, Calvin DC, Chamness SL, et al (1997a) Urinary bladder-urethral sphincter dysfunc tion in mice with targeted disruption of neuronal nitric oxide synthase models idiopathic void ing disorder in humans. Nature Med 3(5):571–574

    CAS  Google Scholar 

  • Burnett AL, Calvin DC, Silver RI, et al (1997b) Immunhistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol 158(1):75–78

    CAS  Google Scholar 

  • Carbone DJ Jr, Hodges S (2003) Medical therapy for benign prostatic hyperplasia: sexual dysfunc tion and impact on quality of life. Int J Impot Res 15:299–306

    PubMed  Google Scholar 

  • Carson CC (2005) cardiac safety in clinical trials of phosophodiesterase 5 inhibitors. Am J Cardiol 96(suppl):37–41

    Google Scholar 

  • Carson CC, Lue TF (2005) Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int 96(3):257–280

    PubMed  CAS  Google Scholar 

  • Caruso S, Intelisano G, Lupo L, et al (2001) Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled study. BJOG 108(6):623–628

    PubMed  CAS  Google Scholar 

  • Caruso S, Rugolo S, Agnello C, et al (2006) Sildenafil improves sexual functioning in pre menopausal women with type 1 diabetes who are affected by sexual arousal disorder: a double-blind, crossover, placebo-controlled pilot study. Fertil Steril 85:1496–1501

    PubMed  CAS  Google Scholar 

  • Chapple CR, Roehrborn CG (2006) A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 49: 651–659

    PubMed  Google Scholar 

  • Chapple C, Khullar V, Gabriel Z, et al (2005) The effects of antimuscarinic treatments inoveractive bladder: a systematic review and meta-analysis. Eur Urol 48:5–26

    PubMed  CAS  Google Scholar 

  • Chen J, Wollman Y, Chernichovsky T, et al (1999) Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled stud. BJU Int 83:269–271

    PubMed  CAS  Google Scholar 

  • Chen KK, Hsieh JT, Huang ST, et al (2001) ASSESS-3: a randomised, double-blind, flexible-dose clinical trial of the efficacy and safety of oral sildenafil in the treatment of men with erectile dysfunction in Taiwan. Int J Impot Res 13(4):221–229

    PubMed  CAS  Google Scholar 

  • Claret L, Cox EH, McFadyen L, et al (2006) Modeling and simulation of sexual activity daily diary data of patients with female sexual arousal disorder treated with sildenafil citrate (Viagra®). Pharm Res 23(8):1756–1764

    PubMed  CAS  Google Scholar 

  • Conners W, Whitebeck C, Chicester P, et al (2006) L-NAME, a nitric oxide synthase inhibitor, diminishes oxidative damage in urinary bladder partial outlet obstruction. Am J Physiol Renal Physiol 290(2):F357–F363

    PubMed  CAS  Google Scholar 

  • Cook AL, Haynes JM (2004) Protein kinase G II-mediated proliferative effects in human cultured prostatic stromal cells. Cell Signal 16(2):253–261

    PubMed  CAS  Google Scholar 

  • Cook AL, Haynes JM (2007) Phosphorylation of the PKG substrate, vasodilator-stimulated phos phoprotein (VASP), in human cultured prostatic stromal cells. Nitric Oxide 16(1):10–17

    PubMed  CAS  Google Scholar 

  • De Tejada IS (2004) Therapeutic strategies for optimizing PDE5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat. Int J Impot Res 216:40–42

    Google Scholar 

  • Dunn ME, Althof SE, Perelman MA (2007) Phosphodiesterase type 5 inhibitors' extended duration of response as a variable in the treatment of erectile dysfunction. Int J Impot Res 19(2):119–123

    PubMed  CAS  Google Scholar 

  • Enzlin P, Mathieu C, Van den Bruel A, et al (2002) Sexual dysfunction in women with type 1 diabetes: a controlled study. Diabetes Care 25(4):672–677

    PubMed  Google Scholar 

  • Esteve SA Laboratorios (2004) WO2004026309

    Google Scholar 

  • Evgenov OV, Pacher P, Schmidt PM, et al (2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5(9): 755–768

    PubMed  CAS  Google Scholar 

  • Ferrini MG, Davila HH, Kovanecz I, et al (2006a) Vardenafil prevents fibrosis and loss of cor poral smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology 68(2):429–435

    Google Scholar 

  • Ferrini MG, Kovanecz I, Nolazco G, et al (2006b) Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease. BJU Int 97(3):625–633

    CAS  Google Scholar 

  • Ferrini MG, Vernet D, Magee TR, Shahed A, Qian A, Rajfer J, Gonzalez-Cadavid NF (2002) Antifibrotic role of inducible nitric oxide synthase. Nitric oxide May; 6(3):283–94

    CAS  Google Scholar 

  • Filippi S, Morelli A, Sandner P, et al (2007) Characterization and functional role of androgen-dependent PDE5 activity in the bladder. Endocrinology 148(3):1019–1029

    PubMed  CAS  Google Scholar 

  • Francis SH, Corbin JD (2005) Phosphodiesterase-5 inhibition: the molecular biology of erectile function and dysfunction. Urol Clin N Am 32:419–429

    Google Scholar 

  • Friebe A, Müllershausen F, Smolenski A, et al (1998) YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol 54(6):962–967

    PubMed  CAS  Google Scholar 

  • Fu Q, Yao DH, Jiang YQ (2001) Effect of sodium nitroprusside on hemodynamics of corpus cav ernosum in Chinese. Asian J Androl 3(4):311–313

    PubMed  CAS  Google Scholar 

  • Gacci M, Del Popolo G, Macchiarella A, et al (2007) Vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study. J Urol 178(5):2040–2043

    PubMed  CAS  Google Scholar 

  • Garbán H, Marquez D, Magee T, et al (1997) Cloning of rat and human inducible penile nitric oxide synthase. Application for gene therapy of erectile dysfunction. Biol Reprod 56(4):954–963

    PubMed  Google Scholar 

  • Gbekor E, Bethell S, Fawcett L, et al (2002) Selectivity of sildenafil and other phosphodiesterase type 5 (PDE5) inhibitors against all human phosphodiesterase families. J Urol 167:63

    Google Scholar 

  • Gillespie JI, Drake MJ (2004) The actions of sodium nitropursside and the phosphdiesterase in hibior dipyridamole on phasic activity in the isolated guinea-pig bladder. BJU Int 93:851–858

    PubMed  CAS  Google Scholar 

  • Gillespie JI, Markerink—van Ittersum M, De Vente J (2006) Endogenous nitric oxide/cGMP sig nalling in the guinea pig bladder: evidence for distinct population of usub-urothelial interstitial cells. Cell Tissue Res 325:325–332

    PubMed  CAS  Google Scholar 

  • Giuliano F, Bernabe J, Alexandre L, et al (2003) Proerectile effect of vardenafil: in vitro experi ments in rabbits and in vivo comparison with sildenafil in rats. Eur Urol 44:731–736

    PubMed  CAS  Google Scholar 

  • Gonzalgo ML, Brotzman M, Trock BJ, et al (2003) Clinical efficacy of sildenafil citrate and pre dictors of long-term response. J Urol 170:503–506

    PubMed  Google Scholar 

  • Gradini R, Realacci M, Ginepri A, et al (1999) Nitric oxide synthases in normal and benign hyperplastic human prostate: immunohistochemistry and molecular biology. J Pathol 189(2): 224–229

    PubMed  CAS  Google Scholar 

  • Gratzke C, Uckert S, Kedia G, et al (2007) In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. Urol Res 35(1):49–54

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Guh JH, Hwang TL, Ko FN, et al (1998) Antiproliferative effect in human prostatic smooth muscle cells by nitric oxide donor. Mol Pharmacol 53(3):467–474

    PubMed  CAS  Google Scholar 

  • Hatzichristou D, Haro JM, Martin-Morales A, et al (2007) Patterns of switching phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction: results from the erectile dysfunction observational study. Int J Clin Pract 61(11):1850–1862

    PubMed  CAS  Google Scholar 

  • Hatzimouratidis K, Hatzichristou D (2007) Phosphodiesterase type 5 inhibitors: the day after. Eur Urol 51(1):75–88

    PubMed  CAS  Google Scholar 

  • Hedlund P, Ekström P, Larsson B, et al (1997) Heme oxygenase and NO-synthase in the human prostate-relation to adrenergic, cholinergic and peptide-containing nerves. J Auton Nerv Syst 63(3):115–126

    PubMed  CAS  Google Scholar 

  • Hellstrom WJ (2006) Current and future pharmacotherapies of preature ejaculation. J Sex Med 3(Suppl 4):332–341

    PubMed  CAS  Google Scholar 

  • Hellstrom WJ (2007) Current safety and tolerability issues in men with erectile dysfunction receiv ing PDE5 inhibitors. Int J Clin Pract 61:1547–1554

    PubMed  CAS  Google Scholar 

  • Hellstrom WJ, Gittelman M, Karlin G, et al (2002) Vardenafil for treatment of men with erec tile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl 23(6):763–771

    PubMed  CAS  Google Scholar 

  • Hernández M, Prieto D, Orensanz LM, et al (1995) Nitric oxide is involved in the non-adrenergic, non-cholinergic inhibitory neurotransmission of the pig intravesical ureter. Neurosci Lett 186(1):33–36

    PubMed  Google Scholar 

  • Heuer O, Ueckert S, Machtens SA, et al (2002) Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro. Urology 59:958–962

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Holmquist F, Stief CG, Jonas U, et al (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

    PubMed  CAS  Google Scholar 

  • Iselin CE, Alm P, Schaad NC, et al (1996) Nitric oxide inhibits contraction of isolated pig ureteral smooth muscle. J Urol 155(2):763–767

    PubMed  CAS  Google Scholar 

  • Iselin CE, Alm P, Schaad NC, et al (1997) Localization of nitric oxide synthase and haemoxyge nase, and functional effects of nitric oxide and carbon monoxide in the pig and human intrav esical ureter. Neurourol 16(3):209–227

    CAS  Google Scholar 

  • Jacobsen SJ, Guess HA, Panser L, et al (1993) A population-based study of health care-seeking behavior for treatment of urinary symptoms. Arch Fam Med 2:729–735

    PubMed  CAS  Google Scholar 

  • Kalsi JS, Rees RW, Hobbs AJ, et al (2003) BAY41-2272, a novel nitric oxide independent solu ble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro. J Urol 169(2):761–766

    PubMed  CAS  Google Scholar 

  • Kalsi JS, Ralph DJ, Madge DJ, et al (2004) A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats. Int J Impot Res 16(6):479–485

    PubMed  CAS  Google Scholar 

  • Kalsi JS, Ralph DJ, Thomas P, et al (2005) A nitric oxide-releasing PDE5 inhibitor relaxes human corpus cavernosum in the absence of endogenous nitric oxide. J Sex Med 2(1):53–57

    PubMed  CAS  Google Scholar 

  • Kaplan SA, Gonzalez RR (2007) Phosphodiesterase type 5 inhibitors for the treatment of male lower urinary tract symptoms. Rev Urol 9(2):73–77

    PubMed  Google Scholar 

  • Kendirci M, Gur S, Sikka SC (2005) Gene therapy for erectile dysfunction. Front Biosci 10: 2758–2769

    PubMed  CAS  Google Scholar 

  • Khan MA, Thompson CS, Mumtaz FH, et al (2000) Urological aspects of female sexual dysfunc tion. Urol Int 65(1):1–8

    PubMed  CAS  Google Scholar 

  • Kim SW, Jeong SJ, Munarriz R, et al (2004) An in vivo rat model to investigate female vaginal arousal response. J Urol 171(3):1357–1361

    PubMed  Google Scholar 

  • Ko FN, Wu CC, Kuo SC, et al (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84(12):4226–4233

    PubMed  CAS  Google Scholar 

  • Kostis JB, Jackson G, Rosen R, et al (2005) Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 96(2):313–321

    PubMed  Google Scholar 

  • Kriegsfeld LJ, Demas GE, Huang PL, et al (1999) Ejaculatory abnormalities in mice lacking the gene for endothelia nitric oxide synthase (eNOS-/-). Physiol Behav 67:561–566

    PubMed  CAS  Google Scholar 

  • Kuciel R, Ostrowski W (1970) Phosphodiesterase from human prostate gland. Bull Soc Chim Biol (Paris) 52(10):1051–1060

    CAS  Google Scholar 

  • Kühn R, Uckert S, Stief CG, et al (2000) Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways. Urol Res. 28(2):110–115

    PubMed  Google Scholar 

  • Kukreja R, Salloum F, Xi L (2007) Anti-ischemic effects of sildenafil, vardenafil and tadalafil in heart. Int J Impot Res 19(2):226–227

    PubMed  CAS  Google Scholar 

  • Laan E, Everaerd W, van der Velde J, et al (1995) Determinants of subjective experience of sexual arousal in women: feedback from genital arousal and erotic stimulus content. Psychophysiol ogy 32(5):444–451

    CAS  Google Scholar 

  • Laumann EO, West S, Glasser D, et al (2007) Prevalence and correlates of erectile dysfunction by race and ethnicity among men aged 40 or older in the United States: from the male attitudes regarding sexual health survey. J Sex Med 4:57–65

    PubMed  Google Scholar 

  • Loughney K, Hill TR, Florio VA, et al (1998) Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase. Gene 216(1):139–147

    PubMed  CAS  Google Scholar 

  • Lue TF (2000) Erectile dysfunction. New Eng J Med 342:1802–1813

    PubMed  CAS  Google Scholar 

  • Machtens S, Ueckert S, Stief CG (2002) Effects of various nitric oxide-donating drugs on adrener gic tension of human seminal vesicles in vitro. Urology 61:479–483

    Google Scholar 

  • Magee TR, Ferrini M, Garban HJ, et al (2002) Gene therapy of erectile dysfunction in the rat with penile neuronal nitric oxide synthase. Biol Reprod 67(3):1033–1041

    PubMed  Google Scholar 

  • Mancina R, Filippi S, Marini M, et al (2005) Expression and functional activity of phosphodi esterase type 5 in human and rabbit vas deferens. Mol Hum Reprod 11:107–115

    PubMed  CAS  Google Scholar 

  • Martina V, Benso A, Gigliardi VR, et al (2006) Short-term dehydroepiandrosterone treatment increases platelet cGMP production in elderly male subjects. Clin Endocrinol (Oxf) 64(3): 260–264

    CAS  Google Scholar 

  • Mastrangelo D, Baertschi AJ, Roatti A, et al (2003) Nitric oxide production within rat urothelial cells. J Urol 170:1409–1414

    PubMed  CAS  Google Scholar 

  • Matsumoto S, Watanabe E, Nakata Y, et al (2007) Bladder protective effects of PDE5 inhibitor: efficacy of vardenafil on rat bladder with outlet obstruction. J Urol 177(suppl):446

    Google Scholar 

  • McMahon CG, Stuckey BGA, Andersen M, et al (2005) Efficacy of sildenafil citrate (Viagra®) in men with premature ejaculation. J Sex Med 2(3):368–375

    PubMed  CAS  Google Scholar 

  • McMahon CG, McMahon CN, Leow LJ, et al (2006) Efficacy of type 5 phosphodiesterase in hibitors in the drug treatment of premature ejaculation: a systematic review. BJU 98:259–272

    CAS  Google Scholar 

  • McVary KT (2007) A review of combination therapy in patients with benign prostatic hyperplasia. Clin Ther 29:387–398

    PubMed  CAS  Google Scholar 

  • McVary KT, Monnig W, Camps JL Jr, et al (2007a) Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms as sociated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 177(3): 1071–1077

    CAS  Google Scholar 

  • McVary KT, Roehrborn CG, Kaminetsky JC, et al (2007b) Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 177(4):1401–1407

    CAS  Google Scholar 

  • Mehrotra N, Gupta M, Kovar A, et al (2007) The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy. Int J Impot Res 19(3):253–264

    PubMed  CAS  Google Scholar 

  • Melman A, Gingel AC (1999) The epidemiology and pathophysiology of erectile dysfunction. J Urol 161:5–11

    PubMed  CAS  Google Scholar 

  • Miller LN, Nakane M, Hsieh GC, et al (2003) A-350619: a novel activator of soluble guanylyl cyclase. Life Sci 72(9):1015–1025

    PubMed  CAS  Google Scholar 

  • Milsom I, Abrams P, Cardozo L, et al (2001) How widespread are the symptoms of the overactive bladder and how are they managed? A population based prevalence study. BJU Int 87:760–766

    PubMed  CAS  Google Scholar 

  • Mizusawa H, Hedlund P, Brioni JD, et al (2002) Nitric oxide independent activation of guanylate cyclase by YC-1 causes erectile response in rat. J Urol 167(5):2276–2281

    PubMed  CAS  Google Scholar 

  • Montague DK, Jarow J, Broderick GA, et al (2004) AUA guideline on the pharmacologic manage ment of preature ejaculation. J Urol 172:290–294

    PubMed  Google Scholar 

  • Mulhall JP, Creech SD, Boorjian SA, et al (2004) Subjective and objective analysis of the preva lence of Peyronie's disease in a population of men presenting for prostate cancer screening. J Urol 171:2350–2353

    PubMed  Google Scholar 

  • Murray K (1993) Phosphodiesterase 5 inhibitors. Drugs News Perspect 3:150–156

    Google Scholar 

  • Najbar-Kaszkiel AT, Di Iulio JL, Li CG, et al (1997) Characterisation of excitatory and inhibitory transmitter systems in prostate glands of rats, guinea pigs, rabbits and pigs. Eur J Pharmacol 337:251–258

    PubMed  CAS  Google Scholar 

  • Oelke M, Hedlund P, Albrecht K, et al (2006) Expression of cAMP and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study. Urology 67(5):1111–1116

    PubMed  Google Scholar 

  • Park K, Moreland RB, Goldstein I, et al (1998) Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem Biophys Res Commun 249(3):612

    PubMed  CAS  Google Scholar 

  • Persson K, Igawa Y, Mattiasson A, et al (1992) Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro. Br J Pharmacol 107:178–184

    PubMed  CAS  Google Scholar 

  • Piediferro G, Colpi EM, Castiglioni F, et al (2004) Preamture ejaculation 3d therapy. Arch Ital Uro Andro 76:192–198

    Google Scholar 

  • Porst H, Padma-Nathan H, Giuliano F, et al (2003) Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 121:5

    Google Scholar 

  • Pryor J, Akkus E, Alter G, et al (2004) Peyronie's disease. J Sex Med 1(1):110–115

    PubMed  Google Scholar 

  • Qiu Y, Kraft P, Craig EC, et al (2001) Identification and functional study of phosphodiesterases in rat urinary bladder. Urol Res 29(6):388–392

    PubMed  CAS  Google Scholar 

  • Qiu Y, Kraft P, Craig EC, et al (2002) Cyclic nucleotide phosphodiesterases in rabbit detrusor smooth muscle. Urology 59(1):145–149

    PubMed  Google Scholar 

  • Rashid A (2005) The efficacy and safety of PDE5 inhibitors. Clin Cornerstone 7:47–56

    PubMed  Google Scholar 

  • Rajfer J, Aronson WJ, Bush PA, et al (1992) Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 326:90–94

    PubMed  CAS  Google Scholar 

  • Roehrborn CG (2002) Reducing the risk of benign prostatic hyperplasia progression. Rev Urol 5:29–38

    Google Scholar 

  • Sadovsky R, Miller T, Moskowitz M, et al (2001) Three-year update of sildenafil citrate (Viagra®) efficacy and safety. Int J Clin Pract 55(2):115–128

    PubMed  CAS  Google Scholar 

  • Sahai A, Khan MS, Arya M, et al (2006b) The overactive bladder: review of current pharmacother apy in adults. Part 1: Pathophysiology and anticholinergic therapy. Expert Opin Pharmacother 7:509–527S

    Google Scholar 

  • Sandner P, Hütter J, Tinel H, et al (2007) PDE5 inhibitors beyond erectile dysfunction. Int J Impot Res 19(6):533–543

    PubMed  CAS  Google Scholar 

  • Schultheiss D, Stief CG (1999) Physiology and pathophysiology of erection: consequences for present medical therapy of erectile dysfunction. Andrologia 31(Suppl 1):59–64

    Article  PubMed  Google Scholar 

  • Schultz KD, Schultz K, Schultz G (1977) Sodium nitroprusside and other smooth muscle relaxants increase cGMP levels in rat ductus deferens. Nature 265:750–751

    PubMed  CAS  Google Scholar 

  • Schwarz-Pharma AG ISIS-Pharma GmBH, (2000) WO2000010542

    Google Scholar 

  • Schwarz ER, Kapur V, Rodriguez J, et al (2007) The effects of chronic phosphodiesterase-5 in hibitor use on different organ systems. Int J Impot Res 19(2):139–148

    PubMed  CAS  Google Scholar 

  • Seftel AD (2004) Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharma cokinetic, and efficacy profiles. Clin Cardiol 27(4Suppl 1):14–19

    Article  Google Scholar 

  • Seidler M, Uckert S, Waldkirch E, et al (2002) In vitro effects of a novel class of nitric oxide (NO) donating compounds on isolated human erectile tissue. Eur Urol 42(5):523–528

    PubMed  CAS  Google Scholar 

  • Shabsigh R (2005) Testosterone therapy in erectile dysfunction and hypogonadism. J Sex Med (6):785–792

    Google Scholar 

  • Shabsigh R, Kaufman JM, Steidle C, et al (2004) Randomized study of testosterone gel as adjunc tive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol 172(2):658–663

    PubMed  CAS  Google Scholar 

  • Singh A, Alter HJ, Littlepage A (2007) A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med 50(5):552–563

    PubMed  Google Scholar 

  • Stacey P, Rulten S, Dapling A, et al (1998) Molecular cloning and expression of human cGMP-binding cGMP-specific phosphodiesterase (PDE5). Biochem Biophys Res Commun 247(2):249–254

    PubMed  CAS  Google Scholar 

  • Stasch JP, Becker EM, Alonso-Alija C, et al (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 8:212–215

    Google Scholar 

  • Stief CG, Holmquist F, Djamilian M, et al (1992) Preliminary results with the nitric oxide donor linsidomine chlorhydrate in the treatment of human erectile dysfunction. J Urol 148(5): 1437–1440

    PubMed  CAS  Google Scholar 

  • Stief CG, Taher A, Truss M, et al (1995) Phosphodiesterase isoenzymes in human ureteral smooth muscle: identification, characterization, and functional effects of various phosphodiesterase in hibitors in vitro. Urol Int 55(4):183–189

    Article  PubMed  CAS  Google Scholar 

  • Stief CG, Uckert S, Truss MC, Becker AJ, et al (1996) A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro. Urol Res 24(6):333–337

    PubMed  CAS  Google Scholar 

  • Stief CG, Porst H, Neuser D, et al (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(6):1236–1244

    PubMed  CAS  Google Scholar 

  • Straub A, Stasch JP, Alonso-Alija C, et al (2001) NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett Mar 11(6):781–784

    CAS  Google Scholar 

  • Taher A, Stief C, Raida M, et al (1992) Cyclic nucleotide phosphodiesterase activity in hu man cavernous smooth muscle and the effect of various selective inhibitors. Int J Impot Res 4(Suppl2):11

    Google Scholar 

  • Taher A, Schulz-Knappe P, Meyer M, et al (1994) Characterization of cyclic nucleotide phos phodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol 12(5):286–291

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Takeda M, Tang R, Shapiro E, et al (1995) Effects of nitric oxide on human and canine prostates. Urology 45(3):440–446

    PubMed  CAS  Google Scholar 

  • Takimoto E, Champion HC, Li M, et al (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11(2):214–222

    PubMed  CAS  Google Scholar 

  • Tejada S, Angulo J, Cellek S, et al (2004) Physiology of erectile function and pathophysiology of eretile dysfunction. Sexual medicine and sexual dysfunction in men and women. Editions 21:289–343

    Google Scholar 

  • Thompson IM, Tangen CM, Goodman PJ, et al (2005) Erectile dysfunction and subsequent cardio vascular disease. JAMA 294 (23):2996–3002

    PubMed  CAS  Google Scholar 

  • Thorpe A, Neal D (2003) Benign prostatic hyperplasia. Lancet 361:1359–1367

    PubMed  CAS  Google Scholar 

  • Tinel H, Sandner P (2008) Vardenafil enhances proceptive and receptive sexual behaviour in the female rat. J Sex Med 5(suppl2):72

    Google Scholar 

  • Tinel H, Huetter J, Sandner P (2006a) PDE5 inhibitors relaxes isolated rat vaginal strips and rat clitoral corpus cavernousum. J Sex Med 3(suppl 5):399

    Google Scholar 

  • Tinel H, Stelte-Ludwig B, Hütter J, et al (2006b) Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms. BJU Int 98(6):1259–1263

    CAS  Google Scholar 

  • Trigo-Rocha F, Aronson WJ, Hohenfellner M, et al (1993) Nitric oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs. Am J Physiol 264:H419–H422

    PubMed  CAS  Google Scholar 

  • Truss MC, Ückert S, Stief CG, et al (1996a) Cyclic nucleotide phosphodiesterase (PDE) isoen-zymes in the human detrusor smooth muscle: I. Identification and characterisation. Urol Res 24:123–128

    CAS  Google Scholar 

  • Truss MC, Ückert S, Stief CG, et al (1996b) Cyclic nucleotide phosphodiesterase (PDE) isoen-zymes in the human detrusor smooth muscle: II. Effect of various PDE-inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. Urol Res 24:123–128

    CAS  Google Scholar 

  • Truss MC, Stief CG, Uckert S, et al (2000) 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(6):439–443

    PubMed  CAS  Google Scholar 

  • Uckert S, Kuthe A, Jonas U, et al (2001) Characterization and functional relevance of cyclic nu cleotide phosphodiesterase isoenzymes of the human prostate. J Urol 166:2484–2490

    PubMed  CAS  Google Scholar 

  • Ückert St, Seemann C, Stief CG, et al (2002) Funktionelle in vitro-effekte cAMP/cGMP mod uliernder Pharmaka am humanen Detrusormuskel. J. Urol Urogynäkol 9:7–14

    Google Scholar 

  • Uckert S, Oelke M, Waldkirch E, et al (2005a) Cyclic adenosine monophosphate and cyclic guano sine monophosphate-phosphodiesterase isoenzymes in human vagina: relation to nitric ox ide synthase isoforms and vasoactive intestinal polypeptide-containing nerves. Urology 65(3): 604–610

    Google Scholar 

  • Uckert S, Ehlers V, Nuser V, et al (2005b) In vitro functional responses of isolated human vaginal tissue to selective phosphodiesterase inhibitors. World J Urol 23(6):398–404

    Google Scholar 

  • Uckert S, Oelke M, Stief CG, et al (2006) Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 49:740–745

    PubMed  Google Scholar 

  • Uckert S, Ellinghaus P, Albrecht K, et al (2007) Expression of messenger ribonucleic acid encoding for phosphodiesterase isoenzymes in human female genital tissues. J Sex Med 4(6):1604–1609

    PubMed  CAS  Google Scholar 

  • Valente EG, Vernet D, Ferrini M, et al (2003) L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie's fibrotic plaque and related fibroblast cultures. Nitric Oxide 9:229–244

    PubMed  CAS  Google Scholar 

  • Vernet D, Ferrini MG, Valente EG, et al (2002) 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(4):262–276

    PubMed  CAS  Google Scholar 

  • Waldkirch ES, Uckert S, Langnäse K, et al (2007) Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1 in human prostate tissue. Eur Urol 52(2):495–501

    PubMed  CAS  Google Scholar 

  • Waldkirch E, Uckert S, Schultheiss D, et al (2008) Non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue. BJU Int 101(1):71–75

    PubMed  Google Scholar 

  • Wang WF, Minhas S, Ralph DJ (2006) Phosphodiesterase 5 inhibitors in the treatment of premature ejaculation. Intl J Androl 29:503–509

    CAS  Google Scholar 

  • Wharton J, Strange JW, Møller GM, et al (2005) Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 172(1):105–113

    PubMed  Google Scholar 

  • Yanaka N, Kotera J, Ohtsuka A (1998) Expression, structure and chromosomal localization of the human cGMP-binding cGMP-specific phosphodiesterase PDE5A gene. Eur J Biochem 255(2):391–399

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Global Drug Discovery — Research Centre Wuppertal, Bayer Schering Pharma, Aprather Weg 18a, Wuppertal, 42069, Germany

    Peter Sandner

  2. Bayer Schering Pharma AG, Global Clinical Development, Pharma Research Center, Wuppertal, 42096, Germany

    Dieter Neuser

  3. Bayer Schering Pharma AG, Cardiology Research, Pharma Research Center, Wuppertal, 42096, Germany

    Erwin Bischoff

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  1. Peter Sandner
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  2. Dieter Neuser
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  3. Erwin Bischoff
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Correspondence to Peter Sandner .

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Editors and Affiliations

  1. Dept. Pharmacology, Monash University, Wellington Road, Clayton, VIC, 3800, Australia

    Harald H. H. W. Schmidt

  2. Inst. Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, München, 80802, Germany

    Franz Hofmann

  3. Bayer Schering Pharma AG Cardiology Research, Pharma Research Center, Wuppertal, 42096, Germany

    Johannes-Peter Stasch

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Sandner, P., Neuser, D., Bischoff, E. (2009). Erectile Dysfunction and Lower Urinary Tract. In: Schmidt, H.H.H.W., Hofmann, F., Stasch, JP. (eds) cGMP: Generators, Effectors and Therapeutic Implications. Handbook of Experimental Pharmacology, vol 191. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-68964-5_22

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