Pharmacology of Phosphodiesterase Inhibitors

  • Erwin Bischoff
Part of the Current Clinical Urology book series (CCU)

Abstract

The second messengers cyclic 3′,5′ adenosine monophosphate (cAMP) and cyclic 3′,5′ guanosine monophosphate (cGMP) play a key role in mediating a variety of functional responses to hormones and other cellular transmitters. Phosphodiesterases (PDEs) are intracellular enzymes that specifically catalyze the hydrolysis of these second messengers. By counterbalancing the enzymes adenylyl cyclase and guanylyl cyclase, which catalyze the formation of cAMP and cGMP, respectively, they regulate the intracellular concentration of both second messengers, thereby influencing a broad variety of physiological functions. PDEs belong to a large superfamily (11 different gene families encode for the PDE families PDE1 to PDE11) of structurally related, functionally distinct, and highly regulated enzymes. Owing to their key roles in physiological processes, PDEs are targets for many drugs that are used for different diseases, such as cardiovascular diseases, asthma, erectile dysfunction (ED), and many others. Increasing knowledge of the molecular biology, regulation, and tissue distribution of this class of enzymes has led to a better understanding of the physiological function of cyclic nucleotides and of the regulatory role of PDEs. This progress was supported by the development of potent PDE inhibitors that are highly selective for one PDE family. Prominent examples are the newly developed selective PDE5 inhibitors, which are discussed here, used for the effective oral treatment of ED.

Keywords

Caffeine PGE1 Theophylline Monophosphate Dyspepsia 

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References

  1. 1.
    Francis S H, Turko IV, Corbin JD. (2001) Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 65:1–52.PubMedCrossRefGoogle Scholar
  2. 2.
    Beavo JA, Conti M, Heaslip RJ. (1994) Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol 46:399–405.PubMedGoogle Scholar
  3. 2a.
    Conti M. (2000) Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol Endocrinol 14:1317–1327.PubMedCrossRefGoogle Scholar
  4. 3.
    Haning H, Niewohner U, Bischoff E. (2003) Phosphodiesterase type 5 (PDE5) inhibitors. Prog Med Chem 41:249–310.PubMedCrossRefGoogle Scholar
  5. 4.
    Mehats C, Andersen CB, Filopanti M, et al. (2002) Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocrinol Metab 13:29–35.PubMedCrossRefGoogle Scholar
  6. 5.
    Manganiello V. (2003) Cyclic nucleotide phosphodiesterase 5 and sildenafil: promises realized. Mol Pharmacol 63:1209–1211.PubMedCrossRefGoogle Scholar
  7. 6.
    Lin CS, Xin ZC, Lin G, et al. (2003) Phosphodiesterases as therapeutic targets. Urology 61:685–691.PubMedCrossRefGoogle Scholar
  8. 7.
    Soderling SH, Beavo JA. (2000) Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol 12:174–179.PubMedCrossRefGoogle Scholar
  9. 8.
    Rytter M. (1973) Impotentia erectionis—therapeutic attempt using bamethan sulfate, synephrine, and coffeinum purum. Z Haut Geschlechtskr 48:481–486.PubMedGoogle Scholar
  10. 9.
    Broughton BJ, Chaplen P, Knowles P, et al. (1974) New inhibitor of reagin-mediated anaphylaxis. Nature 251:650–652.PubMedCrossRefGoogle Scholar
  11. 10.
    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.PubMedCrossRefGoogle Scholar
  12. 11.
    Bush PA, Aronson WJ, Buga GM, et al. (1992) Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J Urol 147:1650–1655.PubMedGoogle Scholar
  13. 12.
    Ignarro LJ, Bush PA, Buga GM, et al. (1990) Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 170:843–850.PubMedCrossRefGoogle Scholar
  14. 13.
    Corbin JD, Francis SH. (1999) Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 274:13,729–13,732.PubMedCrossRefGoogle Scholar
  15. 14.
    Francis SH, Lincoln TM, Corbin JD. (1980) Characterization of a novel cGMP binding protein from rat lung. J Biol Chem 255:620–626.PubMedGoogle Scholar
  16. 15.
    Davis CW, Kuo JF. (1977) Purification and characterization of guanosine 3′:5′-monophosphate-specific phosphodiesterase from guinea pig lung. J Biol Chem 252:4078–4084.PubMedGoogle Scholar
  17. 16.
    Mullershausen F, Russwurm M, Thompson WJ, et al. (2001) Rapid nitric oxide-induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme. J Cell Biol 155:271–278.PubMedCrossRefGoogle Scholar
  18. 17.
    Rybalkin SD, Rybalkina IG, Feil R, et al. (2002) Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem 277:3310–3317.PubMedCrossRefGoogle Scholar
  19. 18.
    Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, et al. (2003) PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J 22:469–478.PubMedCrossRefGoogle Scholar
  20. 19.
    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.PubMedGoogle Scholar
  21. 20.
    Taher A, Stief C, Raida M, et al. (1992) Cyclic nucleotide phosphodiesterase activity in human cavernous smooth muscle and the effect of various selective inhibitors. Int J Impot Res 4(Suppl 2):11.Google Scholar
  22. 21.
    Kuthe A, Wiedenroth A, Magert HJ, et al. (2001) Expression of different phosphodiesterase genes in human cavernous smooth muscle. J Urol 165:280–283.PubMedCrossRefGoogle Scholar
  23. 22.
    Kuthe A, Montorsi F, Andersson KE, et al. (2002) Phosphodiesterase inhibitors for the treatment of erectile dysfunction. Curr Opin Invest Drugs 3:1489–1495.Google Scholar
  24. 23.
    Stief CG. (2000) Phosphodiesterase inhibitors in the treatment of erectile dysfunction. Drugs Today (Barc) 36:93–99.Google Scholar
  25. 24.
    Giordano D, De Stefano ME, Citro G, et al. (2001) Expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in mouse tissues and cell lines using an antibody against the enzyme amino-terminal domain. Biochim Biophys Acta 1539:16–27.PubMedCrossRefGoogle Scholar
  26. 25.
    Kotera J, Fujishige K, Omori K. (2000) Immunohistochemical localization of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in rat tissues. J Histochem Cytochem 48:685–693.PubMedGoogle Scholar
  27. 26.
    Moreland RB, Goldstein II, Kim NN, et al. (1999) Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor. Trends Endocrinol Metab 10:97–104.PubMedCrossRefGoogle Scholar
  28. 27.
    MacGrouther C, Charlton R, Thompson L, et al. (2000) Biochemical In Situ Hybridisation and Immunohestochemical Characterisation of Phosphodiesterase Type 5 Expression in Human Corpus Cavernosum and Cardiac Tissue. Presented at the 9th World Meeting in Impotence Research. Int J Impot Res 27.Google Scholar
  29. 28.
    Lin CS, Chow S, Lau A, et al. (2002) Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters. Int J Impot Res 14:15–24.PubMedCrossRefGoogle Scholar
  30. 29.
    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 216:139–147.PubMedCrossRefGoogle Scholar
  31. 30.
    Taher A, Meyer M, Stief CG, et al. (1997) Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle. World J Urol 15:32–35.PubMedCrossRefGoogle Scholar
  32. 31.
    Schultheiss D, Stief CG. (1999) Physiology and pathophysiology of erection: consequences for present medical therapy of erectile dysfunction. Andrologia 31(Suppl 1):59–64.PubMedGoogle Scholar
  33. 32.
    Saenz de Tejada I, Blanco R, Goldstein I, et al. (1988) Cholinergic neurotransmission in human corpus cavernosum. I. Responses of isolated tissue. Am J Physiol 254:H459–H467.PubMedGoogle Scholar
  34. 33.
    Lue TF, Takamura T, Umraiya M, et al. (1984) Hemodynamics of canine corpora cavernosa during erection. Urology 24:347–352.PubMedCrossRefGoogle Scholar
  35. 34.
    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.PubMedGoogle Scholar
  36. 35.
    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.PubMedCrossRefGoogle Scholar
  37. 36.
    Giuliano F, Bernabe J, Alexandre L, Niewoehner U, Haning H, Bischoff E. (2003) Proerectile effect of vardenafil: in vitro experiments in rabbits and in vivo comparison with sildenafil in rats. Eur. Urol 93:605–608.Google Scholar
  38. 37.
    Goldstein I, Lue TF, Padma-Nathan H, et al. (1998) Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 338:1397–1404.PubMedCrossRefGoogle Scholar
  39. 38.
    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.PubMedCrossRefGoogle Scholar
  40. 39.
    Murray K. (1993) Phosphodiesterase V inhibitors. Drugs News Perspect 3:150–156.Google Scholar
  41. 40.
    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.PubMedCrossRefGoogle Scholar
  42. 41.
    Stasch JP, Becker EM, Alonso-Alija C, et al. (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410:212–215.PubMedCrossRefGoogle Scholar
  43. 42.
    Corbin J D, Turko IV, Beasley A, et al. (2000) Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 267:2760–2767.PubMedCrossRefGoogle Scholar
  44. 43.
    Turko IV, Ballard SA, Francis SH, et al. (1999) Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (type 5) by sildenafil and related compounds. Mol Pharmacol 56:124–130.PubMedGoogle Scholar
  45. 44.
    Gibson A. (2001) Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil. Eur J Pharmacol 411:1–10.PubMedCrossRefGoogle Scholar
  46. 45.
    Saenz de Tejada I, Angulo J, Cuevas P, et al. (2001) The phosphodiesterase inhibitory selectivity and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 13:282–290.PubMedCrossRefGoogle Scholar
  47. 46.
    Angulo J, Gadau M, Fernandez A. (2001) IC351 enhances nitric oxide mediated relaxation of human arterial and trabecular penile smooth muscle. Diabetologia 44:259.CrossRefGoogle Scholar
  48. 47.
    Ballard SA, Gingell CJ, Tang K, et al. (1998) Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 159:2164–2171.PubMedCrossRefGoogle Scholar
  49. 48.
    Bischoff E, Niewöhner U, Haning H, et al. (2001) The inhibitory selectivity of vardenafil on bovine and human recombinant phosphodiesterase isoenzymes. Int J Impot Res 13:41.CrossRefGoogle Scholar
  50. 49.
    Corbin JD, Francis SH. (2002) Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract 56:453–459.PubMedGoogle Scholar
  51. 50.
    Gbekor E, Bethell S, Fawcett L, et al. (2002) Selectivity and other phosphodiesterase type 5 (PDE5) inhibitors against all human phophodiesterase families. Eur Urol Suppl 1:63.Google Scholar
  52. 51.
    Stief CG, Uckert S, Becker AJ, et al. (2000) Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. Urology 55:146–150.PubMedCrossRefGoogle Scholar
  53. 52.
    Bortolotti M, Mari C, Giovannini M, et al. (2001) Effects of sildenafil on esophageal motility of normal subjects. Dig Dis Sci 46:2301–2306.PubMedCrossRefGoogle Scholar
  54. 53.
    Corbin JD, Blount MA, Weeks JL II, et al. (2003) [3H]sildenafil binding to phosphodiesterase-5 is specific, kinetically heterogeneous, and stimulated by cGMP. Mol Pharmacol 63:1364–1372.PubMedCrossRefGoogle Scholar
  55. 54.
    Bischoff E, Mondritzki T, Niewoehner U, et al. (2002) Vardenafil improved erections in rabbits longer than expected from plasma half-life. Int J Impot Res 14(Suppl 4):S7–S42.Google Scholar
  56. 55.
    Berman JR, Berman LA, Lin H, et al. (2001) Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther 27:411–420.PubMedCrossRefGoogle Scholar
  57. 56.
    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 11:367–377.PubMedCrossRefGoogle Scholar
  58. 57.
    Wilkens H, Guth A, Konig J, et al. (2001) Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 104:1218–1222.PubMedCrossRefGoogle Scholar
  59. 58.
    Ghofrani HA, Wiedemann R, Rose F, et al. (2002) Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 136:515–522.PubMedGoogle Scholar
  60. 59.
    Zhihua S. (2003) Phosphodiesterase-5 inhibitors for male erectile dysfunction. Expert Opin Ther Patents 13:1373–1388.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Erwin Bischoff
    • 1
  1. 1.Pharmaceutical Business Group, Institute of Cardiovascular Research IIBayer AGWuppertalGermany

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