Skip to main content
Log in

Phosphodiesterase 5 Inhibitors in Rapid Ejaculation

Potential Use and Possible Mechanisms of Action

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Rapid (premature) ejaculation (RE) is a very common sexual disorder. This condition may be primary or secondary to underlying disease. Control of RE has been primarily focused on behavioural therapy, topical anaesthetics, tricyclic antidepressants and selective serotonin reuptake inhibitors; however, an approved treatment does not exist.

Recently, a number of clinical trials have studied the potential effectiveness of the phosphodiesterase (PDE)-5 inhibitor sildenafil in the treatment of RE. Results of most of these studies have been encouraging. Available data indicate that there is clinical, anatomical, physiological, pharmacological and genetic evidence to explain the efficacy of PDE5 inhibitors in RE. The rationale for the use of PDE5 inhibitors in the treatment of RE could be due to possible peripheral and central mechanisms. Possible peripheral ejaculation retarding capabilities may include modulation of the contractile response of the vas deferens (VD), seminal vesicles (SV), prostate and urethra, induction of a state of peripheral analgesia, and prolongation of the total duration of erection. Possible central mechanisms may involve lessening of the central sympathetic output. Furthermore, there is evidence from knockout mice to explain the efficacy of PDE5 inhibitors in RE. Mice lacking the gene for endothelial nitric oxide synthase develop a condition similar to RE. On the other hand, mice lacking the gene for heme oxygenase-2 develop a condition similar to delayed ejaculation.

This review also discusses the findings against the use of these agents in RE. In conclusion, a review of the literature suggests the potential usefulness of PDE5 inhibitors as a promising line of therapy in RE but further studies are needed.

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

Table I
Table II
Fig. 1
Table III

Similar content being viewed by others

References

  1. Jarow J. Seminal vesicle aspiration in the management of patients with ejaculatory duct obstruction. J Urol 1994; 152: 899–901

    PubMed  CAS  Google Scholar 

  2. Master VA, Turek PJ. Ejaculatory physiology and dysfunction. Urol Clin North Am 2001; 28: 363–75

    PubMed  CAS  Google Scholar 

  3. Vale J. Ejaculatory dysfunction. BJU Int 1999; 83: 557–63

    PubMed  CAS  Google Scholar 

  4. Peterson I, Stener I. An electromyographic study of the striated urethral sphincter, the striated anal sphincter, and the levator ani muscle during ejaculation. Electromyography 1970; 10: 23–44

    Google Scholar 

  5. Elbadawi A, Goodman DC. Autonomic innervation of the accessory male genital glands. In: Spring-Mills E, Hafez ESE, editors. Male accessory sex glands. New York (NY): Elsevier/ North Holland, 1980: 101–28

    Google Scholar 

  6. McConnell J, Benson GS, Wood JG. Autonomic innervation of the urogenital system: adrenergic and cholinergic elements. Brain Res Bull 1982; 9: 679–94

    PubMed  CAS  Google Scholar 

  7. Baumgarten HG, Holstein AF, Rosengren E. Arrangement, ultrastructure, and adrenergic innervation of smooth musculature of the ductuli efferents, ductus epididymidis and ductus deferens of man. Z Zellforsch Mikrosk Anat 1971; 120: 37–79

    PubMed  CAS  Google Scholar 

  8. Kaleczyc J. Origin and neurochemical characteristics of nerve fibres supplying the mammalian vas deferens. Microsc Res Tech 1998; 42: 409–22

    CAS  PubMed  Google Scholar 

  9. Dixon JS, Jen PY, Gosling JA. Structure and autonomie innervation of the human vas deferens: a review. Microsc Res Tech 1998; 42: 423–32

    PubMed  CAS  Google Scholar 

  10. Steers WD. Physiology of the vas deferens. World J Urol 1994; 12: 281–5

    PubMed  CAS  Google Scholar 

  11. Grozdanovic Z, Goessl C. Comparative localization of heme oxygenase-2 and nitric oxide synthase in the autonomie innervation to the human ductus deferens and seminal vesicle. J Urol 1999; 162: 2156–61

    PubMed  CAS  Google Scholar 

  12. Pennefather JN, Lau WA, Mitchelson F, et al. The autonomie and sensory innervation of the smooth muscle of the prostate gland: a review of pharmacological and histological studies. J Auton Pharmacol 2000; 20: 193–206

    PubMed  CAS  Google Scholar 

  13. Jen PY, Dixon JS, Gosling JA. Colocalization of nitric oxide synthase, neuropeptides and tyrosine hydroxylase in nerves supplying the human post-natal vas deferens and seminal vesicle. Br J Urol 1997; 80: 291–9

    PubMed  CAS  Google Scholar 

  14. Ho KM, Ny L, McMurray G, et al. Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the human urethral sphincter. J Urol 1999; 161: 1968–72

    PubMed  CAS  Google Scholar 

  15. Dixon JS, Jen PYP. Development of nerves containing nitric oxide synthase in the human male urogenital organs. Br J Urol 1995; 76: 719–25

    PubMed  CAS  Google Scholar 

  16. Jen PY, Dixon JS, Gosling JA. Colocalization of neuropeptides, nitric oxide synthase and immunomarkers for catecholamines in nerve fibres of the adult human vas deferens. J Anat 1999; 195 (pt 4): 481–9

    PubMed  PubMed Central  Google Scholar 

  17. Hedlund P, Ekstrom P, Larsson B, et al. Heme oxygenase and NO-synthase in the human prostate-relation to adrenergic, cholinergic and peptide containing nerves. J Auton Nerv Syst 1997; 63: 115–26

    PubMed  CAS  Google Scholar 

  18. Haminski HJ, Andrade FH. Nitric oxide: biologic effects on muscle and role in muscle diseases. Neuromuscular Disord 2001; 11: 517–24

    Google Scholar 

  19. Kaleczyc J, Timmermans JP, Majewski M, et al. NO-synthase: containing neurons of the big inferior mesenteric ganglion, part of them innervating the ductus deferens. Acta Anat (Basel) 1994; 151: 62–7

    CAS  Google Scholar 

  20. Djoseland O, Gordeladze JO, Hoglo S, et al. Evidence for androgen-dependent phosphodiesterase activity in rat seminal vesicle and epididymis. Int J Androl 1980; 3: 363–6

    PubMed  CAS  Google Scholar 

  21. Uckert S, Kuthe A, Jonas U, et al. Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol 2001; 166: 2484–90

    PubMed  CAS  Google Scholar 

  22. Yanaka N, Kotera J, Ohtsuka A, et al. Expression, structure and chromosomal localization of human c-GMP-binding cGMP-specific phosphodiesterase PDE5A gene. Eur J Biochem 1998; 255: 391–9

    PubMed  CAS  Google Scholar 

  23. Stacey P, Rulten S, Dapling A, et al. Molecular cloning and expression of human cGMP-binding cGMP-specific phosphodiesterase (PDE5). Biochem Biophys Res Commun 1998; 247: 249–54

    PubMed  CAS  Google Scholar 

  24. Heuer O, Uckert S, Machtens SA, et al. Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro. Urology 2002; 59: 958–62

    PubMed  Google Scholar 

  25. Takeda M, Tang R, Shapiro E, et al. Effects of nitric oxide on human and canine prostates. Urology 1995; 45: 440–6

    PubMed  CAS  Google Scholar 

  26. Andersson K-E, Pascual AG, Persson K, et al. Electrically-induced, nerve-mediated relaxation of rabbit urethra involves nitric oxide. J Urol 1992; 147: 253–9

    PubMed  CAS  Google Scholar 

  27. Kato K, Furuya K, Tsutsui I, et al. Cyclic AMP-mediated inhibition of noradrenaline-induced contraction and Ca2+ influx in guinea-pig vas deferens. Exp Physiol 2000; 85: 387–98

    PubMed  CAS  Google Scholar 

  28. Naseem KM, Mumtaz FH, Thompson CS, et al. Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: modulation by hydrogen peroxide. Eur J Pharmacol 2000; 387: 329–35

    PubMed  CAS  Google Scholar 

  29. Andersson K-E. Neurotransmission and drug effects in urethral smooth muscle. Scand J Urol Nephrol Suppl 2001; 207: 26–34

    Google Scholar 

  30. Schultz KD, Schultz K, Schultz G. Sodium nitroprusside and other smooth muscle relaxants increase cGMP levels in rat ductus deferens. Nature 1977; 265: 750–1

    PubMed  CAS  Google Scholar 

  31. Stjarne L, Bartfai T, Alberts P. The influence of 8-Br 3, 5-cyclic nucleotide analogs and of inhibitors of 3,5-cyclic nucleotide phosphodiesterase, on noradrenaline secretion and neurovascular transmission in guinea-pig vas deferens. Naunyn Schmiedebergs Arch Pharmacol 1979; 308: 99–105

    PubMed  CAS  Google Scholar 

  32. Axelsson KL, Andersson RG, Wikberg JE. Effect of cGMP derivatives on contraction relaxation cycle, release of norepinephrine and protein kinase activity in guinea-pig vas deferens. Acta Pharmacol Toxicol (Copenh) 1980; 47: 328–34

    CAS  Google Scholar 

  33. Beavo J, Conti M, Heaslip RJ. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol 1994; 46: 399–405

    PubMed  CAS  Google Scholar 

  34. Loughney K, Hill TR, Florio VA, et al. Isolation and characterization of cDNAs encoding PDA5A, a human cGMP-binding, cGMP-specific 3,5,-cyclic nucleotide phosphodiesterase. Gene 1998; 216: 139–47

    PubMed  CAS  Google Scholar 

  35. Soderling SH, Bayuga SJ, Beavo JA. Cloning and characterization of a cAMP-Specific cyclic nucleotide phosphodiesterase. Proc Natl Acad sci U S A 1999; 96: 7071–6

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Kotera J, Fujishige K, Omori K. Immunohistochemical localization of cGMP-binding cGM-specific phosphodiesterase (PDE5) in rat tissues. J Histochem Cytochem 2000; 48: 685–93

    PubMed  CAS  Google Scholar 

  37. Giordano D, DeStefano ME, Citro G, et al. Expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in mouse tissues and cell Lines using an antibody against the enzyme amino-terminal domain. Biochem Biophys Acta 2001; 1539: 16–27

    PubMed  CAS  Google Scholar 

  38. Burnett AL, Saito S, Maguire MP, et al. Localization of nitric oxide synthase in spinal nuclei innervating pelvic ganglia. J Urol 1995; 153: 212–7

    PubMed  CAS  Google Scholar 

  39. Terenghi G, Riveros-Moreno V, Hudson LD, et al. Immunohistochemistry of nitric oxide synthase demonstrates immunoreactive neurons in spinal cord and dorsal root ganglia of man and rat. J Neurol sci 1993; 118: 34–7

    PubMed  CAS  Google Scholar 

  40. Melis MR, Argiolas A. Role of central nitric oxide in the control of penile erection and yawning. Prog Neuropsychopharmacol Biol Psychiatry 1997; 21: 899–922

    PubMed  CAS  Google Scholar 

  41. Sato Y, Horita H, Kurohata T, et al. Effect of the nitric oxide level in the medial preoptic area on male copulatory behavior in rats. Am J Physiol 1998; 274: R243–7

    PubMed  CAS  Google Scholar 

  42. Sato Y, Christ JG, Horita H, et al. The effects of alterations in nitric oxide levels in the paraventricular nucleus on copulatory behavior and reflexive erection in male rats. J Urol 1999; 162: 2182–5

    PubMed  CAS  Google Scholar 

  43. Garthwaite J, Boulton CL. Nitric oxide signalling in the central nervous system. Annu Rev Physiol 1995; 57: 683–706

    PubMed  CAS  Google Scholar 

  44. Hull EM, Lumley LA, Matuszewich L, et al. The roles of nitric oxide in sexual function of male rats. Neuropharmacology 1994; 33: 1499–504

    PubMed  CAS  Google Scholar 

  45. Bialy M, Beck J, Abramczyk P, et al. Sexual behavior in male rats after nitric oxide synthesis inhibition. Physiol Behav 1996; 60: 139–43

    PubMed  CAS  Google Scholar 

  46. Pfaus JG. Neurobiology of sexual behavior. Curr Opin Neurobiol 1999; 9: 751–8

    PubMed  CAS  Google Scholar 

  47. Reed S, King M, Watson J. Sexual dysfunction in primary medical care: prevalence, characteristics and detection by the general practitioner. J Public Health Med 1997; 19: 387–91

    Google Scholar 

  48. Masters WH, Johnson VE. Human sexual inadequacy. Boston (MA): Little, Brown & Co, 1970: 92–115

    Google Scholar 

  49. Kaplan HS. How to overcome premature ejaculation. New York (NY): Brunner/Mazel,1989: 5

    Google Scholar 

  50. Obler M. systematic desensitization in sexual disorders. J Behav Ther Exp Psychiatry 1973; 4: 93–6

    Google Scholar 

  51. Waldinger MD, Hengeveld MW, Zwinderman AH, et al. An empirical operationalization study of DSM-IV diagnostic criteria for premature ejaculation. Int J Psychiatr Clin Pract 1998; 2: 287–94

    CAS  Google Scholar 

  52. American Psychiatry Association. Diagnostic and statistical manual of mental disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association, 1994: 509–11

    Google Scholar 

  53. Rowland DL, Cooper SE, Schneider M. Defining premature ejaculation for experimental and clinical investigations. Arch Sex Behav 2001; 30: 235–53

    PubMed  CAS  Google Scholar 

  54. Hendry WF, Althof SE, Benson GS, et al. Male orgasmic and ejaculatory disorders. In: Jardin A, Wagner G, Khoury S, et al., editors. Erectile dysfunction, proceeding of the first international consultation on erectile dysfunction. Plymouth: Health Publications Ltd, 2000: 477–506

    Google Scholar 

  55. Godpodinoff ML. Premature ejaculation: clinical subgroups and etoology. J Sex Marital Ther 1989; 15: 130–4

    PubMed  CAS  Google Scholar 

  56. Fanciullacci F, Colpi GM, Beretta G, et al. Cortical evoked potentials in subjects with true premature ejaculation. Andrologia 1988; 20: 326–30

    PubMed  CAS  Google Scholar 

  57. Xin ZC, Choi YD, Rha KH, et al. Penile sensitivity in patients with primary premature ejaculation. J Urol 1996; 156: 979–81

    PubMed  CAS  Google Scholar 

  58. Xin ZC, Choi YD, Rha KH, et al. Somatosensory evoked potentials in patients with primary premature ejaculation. J Urol 1997; 158: 451–5

    PubMed  CAS  Google Scholar 

  59. Colpi GM, Fanciullacci F, Beretta G, et al. Evoked sacral potentials in subjects with true premature ejaculation. Andrologia 1986; 18: 583–6

    PubMed  CAS  Google Scholar 

  60. Hoehn-Saric R, Mcleod DR. The peripheral sympathetic nervous system: its role in normal and pathologic anxiety. Psychiatr Clin North Am 1988; 11: 375–86

    PubMed  CAS  Google Scholar 

  61. Vickers MA. The forgotten dysfunction: a pharmacological approach to premature ejaculation. In: Morales A, editor. Erectile dysfunction, issues in current pharmacotherapy. London: Martin Dunitz Ltd, 1998: 253–67

    Google Scholar 

  62. Brien SE, Smallegange C, Gofton WT, et al. Development of a rat model of sexual performance anxiety: effect of behavioural and pharmacological hyperadrenergic stimulation on APO-induced erections. Int J Impot Res 2002; 14: 107–15

    PubMed  CAS  Google Scholar 

  63. D’Arbe M, Einstein R, Lavidis NA. Stressful animal housing conditions and their potential effect on sympathetic neurotransmission in mice. Am J Physiol Regul Integr Comp Physiol 2002; 282: R1422–8

    PubMed  Google Scholar 

  64. Peredo H, Agostini MD, Gimeno MF, et al. Hypersensitivity to norepinephrine in Vasa deferentia from diabetic rats: possible participation of metabolic products of arachidonic acid. Prostaglandins Leukot Med 1984; 15: 229–39

    PubMed  CAS  Google Scholar 

  65. Ozturk Y, Yildizoglu-Ari N, Altan VM. Altered alpha-adrenergic responses of vas deferens to noradrenaline and tyramine from rats with short-and long-term alloxan diabetes. Gen Pharmacol 1994; 25: 1519–24

    PubMed  CAS  Google Scholar 

  66. Sakai Y, Aihara K, Honda H, et al. Calcium mobilization and phosphatidylinositol turnover in vas deferens smooth muscle of diabetic rats. Eur J Pharmacol 1989; 162: 475–81

    PubMed  CAS  Google Scholar 

  67. Cellek S, Rodrigo J, Lobos E, et al. Selective nitrergic neurode-generation in diabetes mellitus-a nitric oxide-dependent phenomenon. Br J Pharmacol 1999; 128: 1804–12

    PubMed  PubMed Central  CAS  Google Scholar 

  68. Vernet D, Cai L, Garban H, et al. Reduction of penile nitric oxide synthase in diabetic BB/Wo Rdp (typel) and BBZ/ WoRdp (type II) rats with erectile dysfunction. Endocrinology 1990; 36: 5709–17

    Google Scholar 

  69. El-Sakka AI, Lin CS, Chui RM, et al. Effects of diabetes on nitric oxide synthase and growth factors genes and protein expression in an animal model. Int J Impot Res 1999; 11: 123–32

    PubMed  CAS  Google Scholar 

  70. Kuhr CS, Heiman J, Cardenas D, et al. Premature emission after spinal cord injury. J Urol 1995; 153: 429–31

    PubMed  CAS  Google Scholar 

  71. Marson L, McKenna KH. The identification of a brainstem site controlling spinal sexual reflexes in male rats. Brain Res 1990; 515: 303–8

    PubMed  CAS  Google Scholar 

  72. Mossman S, Kapoor R, Fowler CJ. Spontaneous ejaculation secondary to spinal cord disease. J Neurol Neurosurg Psychiatry 1994; 57: 505–6

    PubMed  PubMed Central  CAS  Google Scholar 

  73. LaBuda CJ, Fuchs PN. Catecholamine depletion by reserpine blocks the anxiolytic actions of ethanol in the rat. Alcohol 2002; 26: 55–9

    PubMed  CAS  Google Scholar 

  74. Boselli C, Govoni S. Effect of in vivo and in vitro ethanol on adrenergic and purinergic responses of the bisected rat vas deferens to low and high frequency pulses. J Auton Pharmacol 2001; 21: 171–9

    PubMed  CAS  Google Scholar 

  75. Rettori V, McCann SM. The Mechanism of action of alcohol to suppress gonadotropin secretion. Mol Psychiatry 1997; 2: 350–4

    PubMed  CAS  Google Scholar 

  76. Pirke KM, Kockott G, Aldenhoff J, et al. Pituitary gonadal system function in patients with erectile dysfunction and premature ejaculation. Arch Sex Behav 1979; 8: 41–8

    PubMed  CAS  Google Scholar 

  77. Motofei IG. The etiology of premature ejaculation starting from a bihormonal model of normal sexual stimulation [letter]. Int J Impot Res 2001; 13: 49–50

    PubMed  CAS  Google Scholar 

  78. Lamas JL, spadari RC. Effect of testosterone on the response of young rat vas deferens to norepinephrine. Gen Pharmacol 1993; 24: 185–9

    PubMed  CAS  Google Scholar 

  79. Penson DF, Ng C, Cai L, et al. Androgen and pituitary control of penile nitric oxide synthase and erectile function in the rat. Biol Reprod 1996; 55: 567–74

    PubMed  CAS  Google Scholar 

  80. Vegeto E, Pollio G, Ciana P, et al. Estrogen blocks inducible nitric oxide synthase accumulation in LPS-activated microglia cells. Exp Gerontol 2000; 35: 1309–16

    PubMed  CAS  Google Scholar 

  81. Screponi E, Carosa E, DiStasi SM, et al. Prevalence of chronic prostatitis in men with premature ejaculation. Urology 2001; 58: 198–202

    PubMed  CAS  Google Scholar 

  82. Park BK, Haynes BP, Sheridan SA, et al. Stereoselectivity of catecholamines: differential effects of cocaine and desipramine on catecholamine: induced contractions of the rat isolated vas deferens. J Pharm Pharmacol 1983; 35: 373–7

    PubMed  CAS  Google Scholar 

  83. Goncalves J, Guimaraes S. Influence of neuronal uptake on pre-and postjunctional effects of alpha-adrenoceptor agonists in tissues with noradrenaline: ATP cotransmission. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 532–7

    PubMed  CAS  Google Scholar 

  84. Wali FA, Greenidge E. Influence of desipramine on the contractile responses to noradrenaline, clonidine and to electrical field stimulation in the rat isolated seminal vesicle. Pharmacol Res 1990; 22: 125–31

    PubMed  CAS  Google Scholar 

  85. Pryor JL, Redman B. New therapies and delivery mechanisms for treatment of erectile dysfunction. Int J Impot Res 2000; 12 Suppl. 4: S158–62

    PubMed  Google Scholar 

  86. Nehra A, Colreavy F, Khandheria BK, et al. Sildenafil citrate, a selective phosphodiesterase type 5 inhibitors: urologic and cardiovascular implications. World J Urol 2001; 19: 40–5

    PubMed  CAS  Google Scholar 

  87. Abdel-Hamid IA, EINaggar EA, ElGilany AH. Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. Int J Impot Res 2001; 13: 41–5

    PubMed  CAS  Google Scholar 

  88. Chen J, Greenstein A, Mabjeesh NJ, et al. Role of sildenafil treatment in premature ejaculation (PE) [abstract 133]. Int J Impot Res 2001; 13 Suppl. 4: 548

    Google Scholar 

  89. Lobik L, Cytron S, Kravchick S, et al. The effect of sildenafil citrate in the treatment of secondary rapid ejaculation [abstract 1414]. J Urol 2003; 169 (4 Suppl.): 378

    Google Scholar 

  90. Chen J, Mabjeesh NJ, Matzkin H, et al. Efficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation. Urology 2003; 61(1): 197–200

    PubMed  Google Scholar 

  91. Salonia A, Maga T, Colombo R, et al. A prospective study comparing paroxetine alone versus paroxetine plus sildenafil in patients with premature ejaculation. J Urol 2002; 168(6): 2486–9

    PubMed  CAS  Google Scholar 

  92. Lozano AF, Castane ER. Premature ejaculation: sildenafil plus sertraline versus sertraline alone and sildenafil alone [abstract 956]. J Urol 2003; 169 (4 Suppl.): 247

    Google Scholar 

  93. Pelligrino DA, Wang Q. Cyclic nucleotide crosstalk and the regulation of cerebral vasodilatation. Progr Neurobiol 1998; 56: 1–18

    CAS  Google Scholar 

  94. Stief CG, Uckert S, Becker AJ, et al. Effects of sildenafil on cAMP and c GMP levels in isolated human cavernous and cardiac tissue. Urology 2000; 55: 146–50

    PubMed  CAS  Google Scholar 

  95. El-Thaher TS, Khatib S, Saleem M, et al. A novel compound JPM8: in vivo penile activity promotion in rats, effect on the relaxation and c GMP/ c AMP accumulation in isolated rabbit corpora cavernosa. Int J Impot Res 2002; 14(6): 453–61

    PubMed  CAS  Google Scholar 

  96. Frith D, Gibson A. Effect of Sildenafil citrate on nitrergic transmission in anococcygeus muscles from the urogenital system of male and female mice. Eur J Pharmacol 2000; 400: 305–12

    PubMed  CAS  Google Scholar 

  97. Vohra MM. Effect of cyclic AMP, db-cyclic AMP and phosphodiesterase inhibitors on histamine inhibition of the contractile response of the mouse vas deferens. Agents Actions 1984; 14: 11–20

    PubMed  CAS  Google Scholar 

  98. Bultmann R, Klebroff W, Starke K. Nucleotide-evoked relaxation of rat vas deferens: possible mechanisms. Eur J Pharmacol 2002; 436: 135–43

    PubMed  CAS  Google Scholar 

  99. Medina P, Segarra G, Torondel B, et al. Inhibition of neuroeffector transmission in human vas deferens by sildenafil. Br J Pharmacol 2000; 131: 871–4

    PubMed  PubMed Central  CAS  Google Scholar 

  100. Machtens S, Uckert S, Stief CG, et al. Effects of various nitric oxide-donating drugs on adrenergic tension of human seminal vesicles in vitro. Urology 2003; 61(2): 479–83

    PubMed  Google Scholar 

  101. Cederquist B, Gustafsson LE. Modulation of neuroeffector transmission in guinea-pig pulmonary artery and vas deferens by exogenous nitric oxide. Acta Physiol Scand 1994; 150: 75–81

    Google Scholar 

  102. Schwarz P, Diem R, Dun NJ, et al. Endogenaus and exogenous nitric oxide inhibits norepinephrine release from rat heart sympathetic nerves. Circ Res 1995; 77: 841–8

    PubMed  CAS  Google Scholar 

  103. Jain NK, Patil CS, Singh A, et al. Sildenafil-induced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Brain Res 2001; 909: 170–8

    PubMed  CAS  Google Scholar 

  104. Asomoza-Espinosa R, Alonso-Lopez R, Mixcoatl-Zecuatl T, et al. Sildenafil increases diclofenac antinociception in the formalin test. Eur J Pharmacol 2001; 418: 195–200

    PubMed  CAS  Google Scholar 

  105. Mixcoatl-Zecuatl T, Aguirre-Banuelos P, Granados-Soto V. Sildenafil produces antinociception and increases morphine antinociception in the formalin test. Eur J Pharmacol 2000; 400: 81–7

    PubMed  CAS  Google Scholar 

  106. Berkovitch M, Keresteci AG, Koren G. Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation. J Urol 1995; 154: 1360–1

    PubMed  CAS  Google Scholar 

  107. Sadovsky R, Miller T, Moskowitz M, et al. Three-year update of sildenafil citrate (Viagra®) efficacy and safety. Int J Clin Pract 2001;55: 115–28

    PubMed  CAS  Google Scholar 

  108. Stark S, Sachse R, Liedl T, et al. Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol 2001; 40: 181–90

    PubMed  CAS  Google Scholar 

  109. Carson CC, Burnett AL, Levine LA, et al. The efficacy of sildenafil citrate (Viagra®) in clinical populations: an update. Urology 2002; 60 (2 Suppl. 2): 12–27

    PubMed  Google Scholar 

  110. Erbagci A, Yagci F, Sarica K, et al. Evaluation and therapeutic regulation of erectile dysfunction with visual stimulation test: an objective approach by using sildenafil citrate test. Urol Int 2002; 69(1): 21–6

    PubMed  Google Scholar 

  111. Eardley I, Ellis P, Boolell M, et al. Onset and duration of action of sildenafil for the treatment of erectle dysfunction. Br J Clin Pharmacol 2002; 53 Suppl. 1: 615–55

    Google Scholar 

  112. Montorsi F, Maga T, Strambi LF, et al. Sildenafil taken at bed time significantly increases nocturnal erections-results of placebo-controlled study. Urology 2000; 56(6): 906–11

    PubMed  CAS  Google Scholar 

  113. Rochira V, Granata AR, Balestrieri A, et al. Effects of sildenafil on nocturnal penile tumescence and rigidity in normal men: randomized, placebo-controlled crossover study. J Androl 2002; 23(4): 566–71

    PubMed  CAS  Google Scholar 

  114. Boolell M, Allen ML, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8(2): 47–52

    PubMed  CAS  Google Scholar 

  115. Kaeya Y, Deguchi A, Yokota Y. Analysis of measured values of ejaculation time in healthy males. J Sex Marital Ther 1997; 23: 25–8

    Google Scholar 

  116. Schultheiss D, Muller SV, Nager W, et al. Central effects of sildenafil (viagra) on auditory selective attention and verbal recognition memory in humans: a study with event-related brain potentials. World J Urol 2001; 19: 46–50

    PubMed  CAS  Google Scholar 

  117. Milman HA, Arnold SB. Neurologic, psychological and aggressive disturbances with sildenafil. Ann Pharmacother 2002; 36: 1129–34

    PubMed  CAS  Google Scholar 

  118. Pu S, Kalra PS, Kalra SP. Diurnal rhythm in cyclic GMP/ nitric oxide efflux in the medial preoptic area of the male rats. Brain Res 1998; 808: 310–2

    PubMed  CAS  Google Scholar 

  119. Bellamy TC, Wood J, Goodwin DA, et al. Rapid desensitization of nitric oxide receptors soluble guanylyl cyclase, underlies diversity of cellular c GMP responses. Proc Natl Acad sci U S A 2000; 97: 2928–33

    PubMed  PubMed Central  CAS  Google Scholar 

  120. Wykes V, Bellamy TC, Garthwaite J. Kinetics of nitric oxide-cyclic GMP signaling in CNS cells and its possible regulation by cyclic GMP. J Neurochem 2002; 83: 37–47

    PubMed  CAS  Google Scholar 

  121. Sakuma L, Togashi H, Yoshioka M, et al. N G Methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis stimulates renal sympathetic nerve activity in vivo: a role for nitric oxide in the central regulation of sympathetic tone. Circ Res 1992; 70: 607–11

    PubMed  CAS  Google Scholar 

  122. Hansen J, Jacobsen TN, Victor RG. Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans? Hypertension 1994; 24: 439–44

    PubMed  CAS  Google Scholar 

  123. Castellana M, Rizzoni D, Beschi M, et al. Relationship between synpathetic nervous system activity, baroreflex and cardiovascular effects after acute nitric oxide synthesis inhibition in human. J Hypertens 1995; 13: 1153–61

    Google Scholar 

  124. Mastsumura K, Abe I, Isuchihashi T, et al. Central nitric oxide attentuates the baroreceptor reflex in conscious rabbits. Am J Physiol 1998; 274: R1142–9

    Google Scholar 

  125. Krukoff TL. Central regulation of autonomic control: no brakes? Clin Exp Pharmacol Physiol 1998; 25: 474–8

    PubMed  CAS  Google Scholar 

  126. Sato Y, Zhao W, Christ GI. Central modulation of the No/c GMP pathway affects the MPOA-induced intracavernous presure response. Am J Physiol Regul Integr Comp Physiol 2001; 281: R269–78

    PubMed  CAS  Google Scholar 

  127. Prickaerts J, VanStaveren WC, Sik A, et al. Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience 2002; 113: 351–61

    PubMed  CAS  Google Scholar 

  128. Paige NM, Hays RD, Litwin MS, et al. Improvement in emotional well-being and relationships of users of sildenafil. J Urol 2001; 166: 1774–8

    PubMed  CAS  Google Scholar 

  129. Baranano DE, Ferris CD, Snyder SH. Atypical neural messengers. Trends Neurosci 2001; 24: 99–106

    PubMed  CAS  Google Scholar 

  130. Ertekin C, Colakoglu Z, Altay B. Hand and genital sympathetic skin potentials in flaccid and erectile penile states in normal potent men and patients with premature ejaculation. J Urol 1995; 153: 76–9

    PubMed  CAS  Google Scholar 

  131. Kriegsfeld LJ, Demas GE, Huang PL, et al. Ejaculatory abnormalities in mice lacking the gene for endothelial nitric oxide synthase (eNos-1-). Physiol Behav 1999; 67: 561–6

    PubMed  CAS  Google Scholar 

  132. Burnett AL. Lecture 2: nitric oxide synthase and heme oxygenase knockout mice: what have we learned? Int J Impot Res 2000; 12 Suppl. 3: S42–4

    PubMed  Google Scholar 

  133. Ingi T, Cheng J, Ronnett GV. Carbon monoxide: an endogenous modulator of the nitric oxide-cyclic GMP signaling system. Neuron 1996; 16: 835–42

    PubMed  CAS  Google Scholar 

  134. Hartsfield CL. Crosstalk between carbon monoxide and nitric oxide. Antioxid Redox Signal 2002; 4: 301–7

    PubMed  CAS  Google Scholar 

  135. Honkala K, Pirila P, Laasonen K. Coadsorption of CO and NO on the Pd (111) surface: combined abinitio and Monte Carlo study. Phys Rev Lett 2001; 86 (26 Pt 1): 5942–5

    PubMed  CAS  Google Scholar 

  136. Ding Y, McCoubrey WK, Maines MD. Interaction of heme oxygenase-2 with nitric oxide donors: is the oxygenase an intracellular “sink” for NO? Eur J Biochem 1999; 264: 854–61

    PubMed  CAS  Google Scholar 

  137. Burnett AL, Johns DG, Kriegfeld LJ, et al. Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med 1998; 4: 84–7

    PubMed  CAS  Google Scholar 

  138. Giuliani D, Ottani A, Ferrari F. Influence of sildenafil on copulatory behaviour in sluggish or normal ejaculator male rats: a central dopamine mediated effect? Neuropharmacology 2002; 42: 562–7

    PubMed  CAS  Google Scholar 

  139. Ottani A, Giuliani D, Ferrari F. Modulatory activity of sildenafil on copulatory behaviour of both intact and castrated male rats. Pharmacol Biochem Behav 2002; 72: 717–22

    PubMed  CAS  Google Scholar 

  140. Diamond J, Janis RA. Increases in cGMP levels may not mediate relaxant effects of sodium nitroprusside, verapamil and hydralazine in rat vas deferens. Nature 1978; 271: 472–3

    PubMed  CAS  Google Scholar 

  141. Patel AI, Hennan JK, Diamond J. Activation of guanosine 3, 5,-cyclic monophosphate-dependent protein kinase in rat vas deferens and distal colon is not accompanied by inhibition of contraction. J Pharmacol Exp Ther 1997; 283: 894–900

    PubMed  CAS  Google Scholar 

  142. Hennan JK, Diamond J. Effect of NO donors on protein phos-phorylation in intact vascular and nonvascular smooth muscles. Am J Physiol Heart Circ Physiol 2001; 280: H1565–80

    PubMed  CAS  Google Scholar 

  143. Aoyagi T, Hayakawa K, Miyaji K, et al. Sildenafil-induced priapism. Bull Tokyo Dent Coll 1999; 40: 215–7

    PubMed  CAS  Google Scholar 

  144. Sur RL, Kane CJ. Sildenafil citrate-associated priapism. Urology 2000; 55: 950

    PubMed  CAS  Google Scholar 

  145. Schachter JB, Wolfe BP. 3-Isobutyl-1-methylxanthine increases alpha-1-adrenergic receptor sensitivity and density in DDT-1-MF2 smooth muscle cells. J Pharmacol Exp Ther 1995; 272: 215–25

    PubMed  CAS  Google Scholar 

  146. Munzel T, Kurz S, Heitzer T, et al. New insights into mechanisms underlying nitrate tolerance. Am J Cardiol 1996; 77: 24C-30C

    Google Scholar 

  147. ElGalley R, Rutland H, Talie R, et al. Long-term efficacy of sildenafil and tachyphylaxis effect. J Urol 2001; 166: 927–31

    CAS  Google Scholar 

  148. Steers WD. Editorial: tachyphylaxis and phosphodiesterase type 5 inhibitors. J Urol 2002; 168: 207

    PubMed  Google Scholar 

  149. Trig-Rocha F, Martinez-Pineiro L, Donatucci CF, et al. Sodium nitroprusside donor in three species. Int J Impot Res 1995; 7: 49–56

    Google Scholar 

  150. Sugimoto J, Hanasaki K, Shintani H. Influence of sodium and potassium ions on the contraction induced by calcium ions in guinea-pig isolated vas deferens. Clin Exp Pharmacol Physiol 1980; 7: 41–4

    PubMed  CAS  Google Scholar 

  151. Usune S, Katsuragi T, Sakamoto Y, et al. Contribution of Na+ and membrane depolarization to contraction induced by adrenaline in the guinea-pig vas deferens. Can J Physiol Pharmacol 1986; 64: 720–3

    PubMed  CAS  Google Scholar 

  152. Drewett JG, Trachte GI, Marchand GR. Atrial natriuretic factor inhibits adrenergic and purinergic neurotransmission in the rabbit isolated vas deferens. J Pharmacol Exp Ther 1989; 248: 134–42

    Google Scholar 

  153. Green IC, Chabrier F-E. Nitric oxide: from basic research to clinical applications. Drug Discov Today 1999; 4: 47–9

    PubMed  CAS  Google Scholar 

  154. Mas M, Fumero B, Fernandez-Vera JR, et al. Neurochemical correlates of sexual exhaustion and recovery as assessed by in vivo microdialysis. Brain Res 1995; 675: 13–9

    PubMed  CAS  Google Scholar 

  155. Becker AJ, Uckert S, Stief CG, et al. Plasma levels of cavernous and systemic norepinephrine and epinephrine in men during different phases of penile erection. J Urol 2000; 164: 573–7

    PubMed  CAS  Google Scholar 

  156. Becker AJ, Uckert S, Stief CG, et al. Systemic and Cavernous plasma levels of vasoactive intestinal polypeptide during sexual arousal in healthy males. World J Urol 2002; 20: 59–63

    PubMed  Google Scholar 

  157. Halaris A. Neurochemical aspects of the sexual response cycle. CNS Spectr 2003; 8(3): 211–6

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ibrahim A. Abdel-Hamid.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abdel-Hamid, I.A. Phosphodiesterase 5 Inhibitors in Rapid Ejaculation. Drugs 64, 13–26 (2004). https://doi.org/10.2165/00003495-200464010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200464010-00002

Keywords

Navigation