Phosphodiesterases in Asthma

  • Hermann Tenor
  • Christian Schudt
Part of the Progress in Inflammation Research book series (PIR)


Airway obstruction and hyperreactivity in asthma are mainly caused by accumulation of inflammatory cells and their mediators promoting bronchoconstriction, airway oedema and airway remodeling. Cyclic AMP counteracts a huge variety of inflammatory cell functions involved in the development and maintenance of asthma. In addition, cyclic AMP has been shown to reverse bronchial constriction, airway oedema and smooth muscle proliferation and may therefore protect against airway remodeling in asthma. cAMP is generated from ATP by adenylate cyclases that are activated by G-protein coupled receptors such as the β2-receptor. In fact, attenuating cAMP generation may aggravate clinical asthma as reported with β2-antagonists. On the other hand, there is overwhelming evidence that β2-agonists improve asthma. However, long-term administration of β2-agonists may be hampered by the phenomenon of tachyphylaxis, e.g. receptor desensitization and post-receptor events. In particular, it was repeatedly demonstrated that continuous use of inhaled β2-agonists is associated with an impairment of their acute protective effects against bronchoconstrictive stimuli [1–4]. Continuous inhalation of β2-agonists impaired their bronchoprotective effect against AMP-induced hyperreactivity to a greater extent compared to hyperreactivity triggered by methacholine. These results may imply that β2-agonists tend to desensitize mast cell responses more strongly than direct smooth muscle responses [4]. Apart from enhanced cAMP generation another option to increase cAMP is to inhibit its decay. Cyclic nucleotide hydrolysing phosphodiesterases (PDE) represent a superfamily of enzymes which break down cAMP and cGMP. Thus PDE inhibitors should increase cAMP in bronchial smooth muscle and inflammatory cells and have anti-asthmatic effects.


PDE4 Inhibitor Cyclic Nucleotide Phosphodiesterase Human Eosinophil Human Alveolar Macrophage PDE4D Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cockcroft DW, O’Byrne PM, Swystun VA, Bhagat R (1995) Regular use of inhaled albuterol and the allergen-induced late asthmatic response. J Allergy Clin Immunol 96: 44–49PubMedCrossRefGoogle Scholar
  2. 2.
    Yates DH, Sussman HS, Shaw MJ, Barnes PJ, Chung KF (1995) Regular formoterol treatment in mild asthma. Effect on bronchial responsiveness during and after treatment. Am J Respir Crit Care Med 152: 1170–1174PubMedGoogle Scholar
  3. 3.
    Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ (1992) Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyper-responsiveness in patients with mild asthma. N Engl J Med 327: 1198–1203PubMedCrossRefGoogle Scholar
  4. 4.
    O’Connor BJ, Aikman SL, Barnes PJ (1992) Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. N Engl J Med 327: 1204–1208PubMedCrossRefGoogle Scholar
  5. 5.
    Butler JM, Chan SC, Stevens S, Hanifin JM (1983) Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol 71: 490–497PubMedCrossRefGoogle Scholar
  6. 6.
    Chan SC, Reifsnyder D, Beavo JA, Hanifin JM (1993) Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J Allergy Clin Immunol 91: 1179–1188PubMedCrossRefGoogle Scholar
  7. 7.
    Gantner F, Tenor H, Gekeler V, Schudt C, Wendel A, Hatzelmann A (1997) Phosphodi-esterase profiles of highly purified human peripheral blood leukoyte populations from normal and atopic individuals: a comparative study. J Allergy Clin Immunol 100: 527–535PubMedCrossRefGoogle Scholar
  8. 8.
    Gantner F, Kupferschmidt R, Schudt C, Wendel A, Hatzelmann (1997) In vitro differentation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumor necrosis factor-alpha release by PDE inhibitors. Br J Pharmacol 121: 221–231PubMedCrossRefGoogle Scholar
  9. 9.
    Tenor H, Hatzelmann A, Kupferschmidt R, Stanciu L, Djukanovic R, Schudt C, Wendel A, Church MK, Shute JK (1995) Cyclic nucleotide phosphodiesterase isoenzyme activities in human alveolar macrophages. Clin Exp Allergy 25: 625–633PubMedCrossRefGoogle Scholar
  10. 10.
    Jiang X, Li J, Paskind M, Epstein PM (1996) Inhibition of calmodulin-dependent phosphodiesterase induces apoptosis in human leukemic cells. Proc Natl Acad Sci USA 93: 1236–1241Google Scholar
  11. 11.
    Rybalkin SD, Bornfeldt KE, Sonnenburg WK, Rybalkina IG, Kwak KS, Hanson K, Krebs EG, Beavo JA (1997) Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J Clin Invest 100: 2611–2621PubMedCrossRefGoogle Scholar
  12. 12.
    Banner KH, Page CP (1996) Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors. Clin Exp Allergy 26 (Suppl 2): 2–9PubMedCrossRefGoogle Scholar
  13. 13.
    Jaffar ZH, Sullivan P, Page C, Costello J (1996) Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 9: 456–462PubMedCrossRefGoogle Scholar
  14. 14.
    Banner KH, Page CP (1995) Immunomodulatory actions of xanthines and isoenzyme selective phosphodiesterase inhibitors. Monaldi Arch Chest Dis 50: 286–292PubMedGoogle Scholar
  15. 15.
    Banner KH, Page CP (1995) Theophylline and selective phosphodiesterase inhibitors as anti-inflammatory drugs in the treatment of bronchial asthma. Eur Respir J 8: 996–1000PubMedGoogle Scholar
  16. 16.
    Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST (1996) Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J 9: 1672–1677PubMedCrossRefGoogle Scholar
  17. 17.
    Djukanovic R, Finnerty JP, Lee C, Wilson S, Madden J, Holgate ST (1995) The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results. Eur Respir J 8: 831–833PubMedGoogle Scholar
  18. 18.
    Tenor H, Hatzelmann A, Church MK, Schudt C, Shute JK (1996) Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. Br J Pharmacol 118: 1727–1735PubMedCrossRefGoogle Scholar
  19. 19.
    Schudt C, Tenor H, Hatzelmann A (1995) PDE Isoenzymes as targets for anti-asthma drugs. Eur Respir J 8: 1179–1183PubMedCrossRefGoogle Scholar
  20. 20.
    Hatzelmann A, Tenor H, Schudt C (1995) Differential effects of non-selective and selective phosphodiesterase inhibitors on human eosinophil functions. Br J Pharmacol 114: 821–831PubMedCrossRefGoogle Scholar
  21. 21.
    Dent G, Giembycz MA, Rabe KF, Wolf B, Barnes PJ, Magnussen H (1994) Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition. Am J Respir Cell Mol Biol 10: 565–572PubMedGoogle Scholar
  22. 22.
    Kidney J, Dominguez M, Taylor PM Rose M, Chung KF, Barnes PJ (1995) Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 151: 1907–1914PubMedGoogle Scholar
  23. 23.
    Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ (1997) A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 337: 1412–1418PubMedCrossRefGoogle Scholar
  24. 24.
    Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A, Steinijans VW (1997) Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 10: 2754–2760PubMedCrossRefGoogle Scholar
  25. 25.
    Reeves ML, Leigh BK, England PJ (1987) The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J 214: 535–541Google Scholar
  26. 26.
    Rocque WJ, Holmes WD, Patel IR, Dougherty RW, Ittoop O, Overton L, Hoffman CR, Wisely GB, Willard DH, Luther MA (1997) Detailed characterization of a purified type 4 phosphodiesterase, HSPDE4B2B: differentiation of high-and low-affinity (R)-rolipram binding. Protein Expr Purif 9: 191–202PubMedCrossRefGoogle Scholar
  27. 27.
    Souness JE, Griffin M, Maslen C, Ebsworth K, Scott LC, Pollock K, Palfreyman MN, Karlsson JA (1996) Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a “low-affinity” phosphodiesterase 4 conformer. Br J Pharmacol 118: 649–658PubMedCrossRefGoogle Scholar
  28. 28.
    Barnette MS, Bartus JO, Burman M, Christensen SB, Cieslinski LB, Esser KM, Prabhakar US, Rush JA, Torphy TJ (1996) Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H]rolipram binding. Biochem Pharmacol 51: 949–956PubMedCrossRefGoogle Scholar
  29. 29.
    Souness JE, Houghton C, Sardar N, Withnall MT (1997) Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin-2 release from murine splenocytes by interaction with a “low-affinity” phosphodiesterase 4 conformer. Br J Pharmacol 121: 743–750PubMedCrossRefGoogle Scholar
  30. 30.
    Barnette MS, Manning CD, Cieslinski LB, Burman M, Christensen SB, Torphy TJ (1995) The ability of phosphodiesterase IV inhibitors to suppress Superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity. J Pharmacol Exp Ther 273: 674–679PubMedGoogle Scholar
  31. 31.
    Underwood DC, Osborn RR, Novak LB, Matthews JK, Newsholme SJ, Undem BJ, Hand J, Torphy TJ (1993) Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram. J Pharmacol Exp Ther 266: 306–313PubMedGoogle Scholar
  32. 32.
    Essayan DM, Huang SL, Undem BJ, Kagey-Sobotka A, Lichtenstein LM (1994) Modulation of antigen-and mitogen-induced proliferative responses of peripheral blood mononuclear cells by nonselective and isoenzyme selective cyclic nucleotide phosphodiesterase inhibitors. J Immunol 153: 3408–3416PubMedGoogle Scholar
  33. 33.
    Barnette MS, Christensen SB, Underwood DC, Torphy TJ (1996) Phosphodiesterase 4: Biological underpinnings for the design of improved inhibitors. Pharmacol Rev Comm 8: 65–73Google Scholar
  34. 34.
    Hughes B, Owens R, Perry M, Warrelow G, Allen R (1997) PDE4 inhibitors: the use of molecular cloning in the design and development of novel drugs. Drug Dis Today 2: 89–401CrossRefGoogle Scholar
  35. 35.
    Schmiechen R, Schneider HH, Wachtel H (1990) Close correlation between behavioural response and binding in vivo for inhibitors of the rolipram-sensitive phosphodiesterase. Psychopharmacol 102: 17–20CrossRefGoogle Scholar
  36. 36.
    Duplantier AJ, Biggers MS, Chambers RJ, Cheng JB, Cooper K, Damon DB, Eggler JF, Kraus KG, Marfat A, Masamune H et al (1996) Biarylcarboxylic acids and amides: inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behaviour in the ferret. J Med Chem 39: 120–125PubMedCrossRefGoogle Scholar
  37. 37.
    Barnette MS, Grous M, Cieslinski LB, Burman M, Christensen SB, Torphy TJ (1995) Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site. J Pharmacol Exp Ther 273: 1396–1402PubMedGoogle Scholar
  38. 38.
    Harris AL Connell MJ, Ferguson EW, Wallace AM, Gordon RJ Pagani ED, Silver PJ (1989) Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relexation and bronchodilation in the guinea pig. J Pharmacol Exp Ther 251: 199–206PubMedGoogle Scholar
  39. 39.
    Jacobitz, S, Ryan MD, Mc Laughlin MM, Livi GP, DeWolf WE, Torphy TJ (1997) Role of conserved histidines in catalytic activity and inhibitor binding of human recombinant phosphodiesterase 4A. Mol Pharmacol 51: 999–1006PubMedGoogle Scholar
  40. 40.
    Rocque WJ, Tian G, Wiseman JS, Holmes WD, Zajac-Thompson I, Willard DH, Indravaden R, Patel G, Wisely B, Clay WC et al (1997) Human recombinant phosphodiesterase 4B2B binds (R)-rolipram at a single site with two affinities. Biochemistry 36: 14250–14261PubMedCrossRefGoogle Scholar
  41. 41.
    Torphy TJ, Christensen SB, Barnette MS, Burman M., Cieslinski LB, DeWolf WE (1997) Molecular basis for an improved therapeutic index of SB 207499, a second generation phosphodiesterase 4 inhibitor. Eur Respir J 10 (Suppl 25): 3135Google Scholar
  42. 42.
    Alvarez R, Sette C, Yang D, Eglen R, Wilhelm R, Shelton ER, Conti M (1995) Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3. Mol Pharmacol 48: 616–622PubMedGoogle Scholar
  43. 43.
    Sette C, Conti M (1996) Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. J Biol Chem 271: 16526–16530PubMedCrossRefGoogle Scholar
  44. 44.
    Huston E, Pooley L, Julien P, Scotland G, McPhee I, Sullivan M, Bolger G, Houslay MD (1996) The human cyclic AMP-specific phosphodiesterase PDE-46 (HSPDE4A4B) expressed in transfected COS7 cells occurs as both particulate and cytosolic species that exhibit distinct kinetics of inhibition by the antidepressant rolipram. J Biol Chem 271: 31334–31344PubMedCrossRefGoogle Scholar
  45. 45.
    Kelly JJ, Barnes PJ, Giembycz MA (1996) Phosphodiesterase 4 in macrophages: relationship between cAMP accumulation, suppression of cAMP hydrolysis and inhibition of [3H]R-(-)rolipram binding by selective inhibitors. Biochem J 318: 425–436PubMedGoogle Scholar
  46. 46.
    Souness JE, Rao S (1997) Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal 9: 227–236PubMedCrossRefGoogle Scholar
  47. 47.
    Souness JE, Scott LC (1993) Stereospecifity of rolipram actions on eosinophil cyclic AMP-specific phosphodiesterase. Biochem J 291: 389–395PubMedGoogle Scholar
  48. 48.
    Souness JE, Maslen C, Scott LC (1992) Effects of solubilization and vanadate/glutathione complex on inhibitor potencies against eosinophil cyclic AMP-specific phosphodiesterase. FEBS Lett 302: 181–184PubMedCrossRefGoogle Scholar
  49. 49.
    Stringfield TM, Morimoto BH (1997) Modulation of cyclic AMP levels in a clonal neural cell line by inhibitors of tyrosine phosphorylation. Biochem Pharmacol 53: 1271–1278PubMedCrossRefGoogle Scholar
  50. 50.
    Ogiwara T, Chik CL, Ho AK (1997) Tyrosine kinase inhibitors enhance GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells. J Endocrinol 152: 193–199PubMedCrossRefGoogle Scholar
  51. 51.
    Ho A, Wiest R, Ogiwara T, Murdoch G, Chik CL (1995) Potentiation of agonist-stimulated cyclic AMP accumulation by tyrosine kinase inhibitors in rat pinealocytes. J Neurochem 65: 1597–1603PubMedCrossRefGoogle Scholar
  52. 52.
    Dent G, Munoz NM, Zhu X, Rühlmann E, Leff AR, Magnussen H, Rabe KF (1997) Tyrosine kinase inhibition by genistein blocks PAF-induced respiratory burst and leukotriene C4 production in human eosinophils. Eur Resp J 10 (Supp 25): 265sGoogle Scholar
  53. 53.
    Taylor CC, Limback D, Terranova PF (1997) Src tyrosine kinase activity in rat thecal-interstitial cells and mouse TM3 Leydig cells is positively associated with cAMP-specific phosphodiesterase activity. Mol Cell Endocrinol 126: 91–100PubMedCrossRefGoogle Scholar
  54. 54.
    O’Connell JC, McCallum JF, McPhee I, Wakefield J, Houslay ES, Wishart W, Bolger G, Frame M, Houslay MD (1996) The SH3 domain of Src tyrosyl protein kinase interacts with the N-terminal splice region of the PDE4A cAMP-specific phosphodiesterase RPDE-6 (RNPDE4A5). Biochem J 318: 255–261PubMedGoogle Scholar
  55. 55.
    Masamune H, Cheng JB, Cooper K, Eggler JF, Marfat A, Marshall SC, Shirley JT, Tickner JE, Umland JP, Vazquez E (1995) Discovery of micromolar PDE4 inhibitors that exhibit much reduced affinity for the [3H]rolipram binding site: 3-norbomyloxy-4-methoxyphenylmethylene oxindoles. Bioorgan & Med Chem Lett 5: 1965–1968CrossRefGoogle Scholar
  56. 56.
    Cheng JB, Cooper K, Duplantier AF, Eggler JF, Kraus KG, Marshall SC, Marfat A, Masamune H, Shirley J et al (1995) Synthesis and in vitro profile of a novel series of catechol benzimidazoles. The discovery of potent, selective phosphodiesterase type IV inhibitors with greatly attenuated affinity for the [3H]rolipram binding site. Bioorgan & Med Chem Lett 5: 1969–1972CrossRefGoogle Scholar
  57. 57.
    Livi GP, Kmetz P, McHale MC, Cieslinski LB, Sathe GM, Taylor DP, Davis RL, Torphy TJ, Balcarek JM (1990) Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase. Mol Cell Biol 6: 2678–2686Google Scholar
  58. 58.
    Bolger C, Michaelil T, Martin T, St. John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K (1993) A family of human phosphodiesterases homologous to the dunce learning and memory gene product of drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol 13: 6558–6571PubMedGoogle Scholar
  59. 59.
    Jacobitz S, McLaughlin MM, Livi GP, Burman M, Torphy TJ (1996) Mapping the functional domains of human recombinant phosphodiesterase 4A: structural requirements for catalytic activity and rolipram binding. Mol Pharmacol 50: 891–899PubMedGoogle Scholar
  60. 60.
    Owens RJ, Catterall C, Batty D, Jappy J, Russell A, Smith B, O’Connell J, Perry MJ (1997) Human phosphodiesterase 4A: characterization of full-length and truncated enzymes expressed in COS cells. Biochem J 326: 53–60PubMedGoogle Scholar
  61. 61.
    Manning CD McLaughlin MM, Livi GP, Cieslinski B, Torphy TJ, Barnette MS (1996) Prolonged Beta-adrenoceptor stimulation up-regulates cAMP phosphodiesterase activity in human monocytes by increasing mRNA and protein for phosphodiesterases 4A and 4B. J Pharmacol Exp Ther 276: 810–818PubMedGoogle Scholar
  62. 62.
    Percival MD, Yeh B, Falgueyret JP (1997) Zinc dependent activation of cAMP-specific phosphodiesterase (PDE4A). Biochem Biophys Res Comm 241: 175–180PubMedCrossRefGoogle Scholar
  63. 63.
    Houslay M, Scotland G, Erdogan S, Huston E, Mackenzie S, McCallum J, McPhee I, Pooley L, Rena G, Ross A et al. (1996) Intracellular targeting, interaction with Src homology 3 (SH3) domains and rolipram-detected conformational switches in cAMP-specific PDE4A phosphodiesterase. Biochem Soc Trans 25: 374–379Google Scholar
  64. 64.
    Houslay MD (1996) The N-terminal alternately spliced regions of PDE4A cAMP-specific phosphodiesterases determine intracellular targeting and regulation of catalytic activity. Biochem Soc Trans 24: 980–986PubMedGoogle Scholar
  65. 65.
    Sun G, Ke S, Budde RJ (1997) Csk phosphorylation and inactivation in vitro by the cAMP-dependent protein kinase. Arch Biochem Biophys 343: 194–200PubMedCrossRefGoogle Scholar
  66. 66.
    Iwabuchi K, Hatakeyama S, Takahashi A, Ato M, Okada M, Kajino Y, Kajino K, Ogasawara K, Takami K, Nakagawa H et al. (1997) CsK overexpression reduces several monokines and nitric oxide productions but enhances prostaglandin E2 production in response to lipopolasaccharide in the macrophage cell line J774A.1. Eur J Immunol 27: 742–749PubMedCrossRefGoogle Scholar
  67. 67.
    Thomson AW, Bonham C, Zeevi A (1995) Mode of action of tracrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 6: 584–591CrossRefGoogle Scholar
  68. 68.
    Itoh S, Navia MA (1995) Structure comparison of native and mutant human recombinant FKBP12 complexes with the immunosuppresssant drug FK506 (tracolimus). Protein Sci 11: 2261–2268CrossRefGoogle Scholar
  69. 69.
    Onofri F, Giovedi S, Vaccaro P, Czernik AP, Valtorta F, De Camilli P, Greengard P, Benfenati F (1997) Synapsin I interacts with c-Src and stimulates its tyrosine kinase activity. Proc Natl Acad Sci 94: 12168–12173PubMedCrossRefGoogle Scholar
  70. 70.
    Verghese MW, McDonnell RT, Lenhard JM, Hamacher L, Jin SLC (1995) Regulation of distinct cyclic AMP-specific phosphodiesterase (phosphodiesterase Type 4) isozymes in human monocytic cells. Mol Pharmacol 47: 1164–1171PubMedGoogle Scholar
  71. 71.
    Miyazaki T, Taniguchi T (1996) Coupling of the IL2 receptor complex with non-receptor protein tyrosine kinases. Cancer Surv 27: 25–40PubMedGoogle Scholar
  72. 72.
    Beaty CD, Franklin TL, Uehara Y, Wilson CB (1994) Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction. Eur J Immunol 24: 1278–1284PubMedCrossRefGoogle Scholar
  73. 73.
    Schlottmann KE, Gulbins E, Lau SM, Coggeshall KM (1996) Activation of Src-family tyrosine kinases during Fas-induced apoptosis. J Leukoc Biol 60: 546–554PubMedGoogle Scholar
  74. 74.
    Yousefi S, Hoessli DC, Blaser K, Mills GB, Simon HU (1996) Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils. J Exp Med 183: 1407–1414PubMedCrossRefGoogle Scholar
  75. 75.
    Kato M, Kita H, Morikawa A (1997) Role of tyrosine kinases in human eosinophil degranulation. Int Arch Allergy Immunol 114 (Suppl 1): 14–17PubMedCrossRefGoogle Scholar
  76. 76.
    Ashton MJ, Cook DC, Fenton G, Karlsson JA, Palfreyman MN, Raeburn D, Ratcliffe AJ, Souness JE, Thurairatnam S, Vicker N (1994) Selective type IV phosphodiesterase inhibitors as antiasthmatic agents. The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues. J Med Chem 37: 1696–1703PubMedCrossRefGoogle Scholar
  77. 77.
    Souness JE, Maslen C, Webber S, Foster M, Raeburn D, Palfreyman MN, Ashton MJ, Karlsson JA (1995) Suppression of eosinophil function by RP73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. Br J Pharmacol 115: 39–46PubMedCrossRefGoogle Scholar
  78. 78.
    Jacobitz S, McLaughlin MM, Livi GP, Ryan MD, Torphy TJ (1994) The role of conserved histidine residues on cAMP hydrolyzing activity and rolipram binding of human phosphodiesterase IV. FASEB J 8: A371Google Scholar
  79. 79.
    Shakur Y, Wilson M, Pooley L, Lobban M, Griffiths S, Campbell A, Beattie J, Daly S, Houslay M (1995) Identification and characterization of the type-IVA cyclic AMP-specific phosphodiesterase RDI as a membrane-bound protein expressed in cerebellum. Biochem J 306: 801–809PubMedGoogle Scholar
  80. 80.
    Shakur Y, Pryde JG, Houslay MD (1993) Engineered deletion of the unique N-terminal domain of the cyclic AMP-specific phosphodiesterase RD1 prevents plasma membrane association and the attainment of enhanced thermostability without altering its sensitivity to inhibition by rolipram. Biochem J 292: 677–686PubMedGoogle Scholar
  81. 81.
    McPhee I, Pooley L, Lobban M, Bolger G, Houslay MD (1995) Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem J 310: 965–974PubMedGoogle Scholar
  82. 82.
    Pooley L, Shakur Y, Rena G, Houslay MD (1997) Intracellular localization of the PDE4A cAMP-specific phosphodiesterase splice variant RD1 (RNPDE4A1A) in stably transfected human thyroid carcinoma FTC cell lines. Biochem J 321: 177–185PubMedGoogle Scholar
  83. 83.
    Scotland G, Houslay M (1995) Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1A; rPDE-IVA1) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyl-transferase. Biochem J 308: 673–681PubMedGoogle Scholar
  84. 84.
    McLaughlin MM, Cieslinski LB, Burman M, Thorphy TJ, Livi GP (1993) A low-Km, rolipram sensitive, cAMP-specific phosphodiesterase from human brain. J Biol Chem 268: 6470–6476PubMedGoogle Scholar
  85. 85.
    Obernolte R, Bhakta S, Alvarez R, Bach C, Zuppan P, Mulkins M, Jarnagin K, Shelton ER (1993) The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family. Gene 129: 239–247PubMedCrossRefGoogle Scholar
  86. 86.
    Huston E, Lumb S, Russell A, Catterall C, Ross AH, Steele MR, Bolger GB, Perry MJ, Owens RF, Houslay MD (1997) Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase HSPDE4B3. Biochem J 328: 549–558PubMedGoogle Scholar
  87. 87.
    Lobban M, Shakur Y, Beattie J, Houslay MD (1994) Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions. Biochem J 304: 399–406PubMedGoogle Scholar
  88. 88.
    Pillai R, Kytle K, Reyes A, Colicelli J (1993) Use of a yeast expression system for the isolation and analysis of drug-resistant mutants of a mammalian phosphodiesterase. Proc Natl Acad Sci 90: 11970–11974PubMedCrossRefGoogle Scholar
  89. 89.
    Engels P, Sullivan M, Muller T, Lubbert H (1995) Molecular cloning and functional expression in yeast of human cAMP-specific phosphodiesterase subtype (PDE IV-C). FEBS-Lett 358: 305–310PubMedCrossRefGoogle Scholar
  90. 90.
    Engels P, Fichtel K, Lubbert H (1994) Expression and regulation of human and rat phosphodiesterase type IV isogenes. FEBS Lett 350: 291–295PubMedCrossRefGoogle Scholar
  91. 91.
    Obernolte R, Ratzliff J, Baecker PA, Daniels DV, Zuppan P, Jarnagin K, Shelton ER (1997) Multiple splice variants of phosphodiesterase PDE4C cloned from human lung and testis. Biochem Biophys Acta 1353: 287–297PubMedCrossRefGoogle Scholar
  92. 92.
    Swinnen JV, Joseph DR, Conti M (1989) Molecular cloning of rat homologues of the drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. Proc Natl Acad Sci 86: 5325–5329PubMedCrossRefGoogle Scholar
  93. 93.
    Monaco L, Vicini E, Conti M (1994) Structure of two rat genes coding for closely related rolipram-sensitive cAMP phosphodiesterases. Multiple mRNA variants originate from alternative and multiple start sites. J Biol Chem 269: 347–357PubMedGoogle Scholar
  94. 94.
    Conti M, Iona S, Cuomo M, Swinnen J, Odeh J, Svoboda M (1995) Characterization of a hormon-inducible, high affinity adenosine 3′-5′-cyclic monophosphate phosphodiesterase from the rat Sertoli cell. Biochemistry 34: 7979–7987PubMedCrossRefGoogle Scholar
  95. 95.
    Baecker PA, Obernolte R, Bach C, Yee C, Shelton ER (1994) Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD). Gene 138: 253–256PubMedCrossRefGoogle Scholar
  96. 96.
    Nemoz G, Zhang R, Sette C, Conti M (1996) Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells. FEBS Lett 384: 97–102PubMedCrossRefGoogle Scholar
  97. 97.
    Truong V, Muller T (1994) Isolation, biochemical characterization and N-terminal sequence of rolipram-sensitive cAMP phosphodiesterase from human mononuclear leukocytes. FEBS Lett 353: 113–118PubMedCrossRefGoogle Scholar
  98. 98.
    Giembycz MA, Corrigan CJ, Seybold J, Newton R, Barnes PJ (1996) Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol 118: 1945–1958PubMedCrossRefGoogle Scholar
  99. 99.
    Essayan DM, Kagey-Sobotka A, Lichtenstein LM, Huang SK (1997) Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isoenzyme selective cyclic nucleotide phosphodiesterase inhibitors. J Pharmacol Exp Ther 282: 505–512PubMedGoogle Scholar
  100. 100.
    Erdogan S, Houslay MD (1997) Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant. Biochem J 321: 165–175PubMedGoogle Scholar
  101. 101.
    Bolger GB, Erdogan S, Jones R, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell S, Houslay MD (1997) Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J 328: 539–548PubMedGoogle Scholar
  102. 102.
    Kovala R, Sanwal BD, Ball EH (1997) Recombinant expression of a type IV, cAMP-specific phosphodiesterase: characterization and structure-function studies of deletion mutants. Biochemistry 36: 2968–2976PubMedCrossRefGoogle Scholar
  103. 103.
    Torphy TJ, Stadel JM, Burman M, Cieslinski LB, McLaughlin MM, White JR, Livi GP (1992) Coexpression of human cAMP-specific phosphodiesterase activity and high affinity rolipram binding in yeast. J Biol Chem 267: 1798–1804PubMedGoogle Scholar
  104. 104.
    Conti M, Geremia R, Adamo S, Stefanini M (1981) Regulation of Sertoli cell cyclic adenosine 3′: 5′-monophosphate phosphodiesterase activity by follicle stimulating hormone and dibutyryl cyclic AMP. Biochem Biophys Res Commun 98: 1044–1050PubMedCrossRefGoogle Scholar
  105. 105.
    Torphy TJ, Zhou HL, Cieslinski LB (1992) Stimulation of beta adrenoceptors in a human monocyte cell line (U937) up-regulates cyclic AMP-specific phosphodiesterase activity. J Pharmacol Exp Ther 263: 1195–1205PubMedGoogle Scholar
  106. 106.
    Haider S, Smith C, Cui Y, Ding J, Bentley-Hibbert S, Kmal G, Moggio R, Stemerman M (1995) Cyclic AMP-mediated induction of low Km cyclic AMP phosphodiesterase in rat aortic smooth muscle. FASEB J 9 A678Google Scholar
  107. 107.
    Rose R, Liu H, Palmer D, Maurice D (1997) Cyclic AMP-mediated regulation of vascular smooth muscle cell cyclic AMP phosphodiesterase activity. Br J Pharmacol 122: 233–240PubMedCrossRefGoogle Scholar
  108. 108.
    Kochetkova M, Burns F, Souness J (1995) Isoprenaline induction of cAMP-phosphodiesterase in guinea pig macrophages occurs in the presence, but not in the absence, of the phosphodiesterase type IV inhibitor rolipram. Biochem Pharmacol 50: 2033–2038PubMedCrossRefGoogle Scholar
  109. 109.
    Tenor H, Hatzelmann A, Wendel A, Schudt C (1995) Identification of phosphodiesterase IV activity and its cyclic adenosine monophosphate-dependent up-regulation in a human keratinocyte cell line (HaCaT). J Invest Dermatol 105: 70–74PubMedCrossRefGoogle Scholar
  110. 110.
    Kovala T, Lorimer I, Brickenden A, Ball E, Sanwal B (1994) Protein kinase A regulation of cAMP phosphodiesterase expression in rat skeletal myoblasts. J Biol Chem 269: 8680–8685PubMedGoogle Scholar
  111. 111.
    Chang Y, Conti M, Lee Y, Lai H, Ching Y, Chern Y (1997) Activation of phosphodiesterase IV during desensitization of the A2A adenosine receptor-mediated cyclic AMP response in rat pheochromocytoma (PC12) cells. J Neurochem 69: 1300–1309PubMedCrossRefGoogle Scholar
  112. 112.
    Swinnen J, Joseph D, Conti M (1989) The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP. Proc Natl Acad Sci 86: 8197–8201PubMedCrossRefGoogle Scholar
  113. 113.
    Swinnen J, Tsikalas K, Conti M (1991) Properties and hormonal regulation of two structurally related cAMP phosphodiesterases from the rat Sertoli cell. J Biol Chem 266: 18370–18377PubMedGoogle Scholar
  114. 114.
    Sette C, Vicini E, Conti M (1994) The rat PDE3/IVD phosphodiesterase gene codes for multiple proteins differentially activated by cAMP-dependent protein kinase. J Biol Chem 269: 18271–18274PubMedGoogle Scholar
  115. 115.
    Torphy T, Zhou H, Foley J, Sarau H, Manning C, Barnette M (1995) Salbutamol up-regulates PDE4 activity and induces a heterologous desensitization of U937 cells to prostaglandin E2. Implications for the therapeutic use of beta-adrenoceptor agonists. J Biol Chem 270: 23598–23604PubMedCrossRefGoogle Scholar
  116. 116.
    Vicini E, Conti M (1997) Characterization of an intronic promoter of a cyclic adenosine 3′, 5′-monophosphate (cAMP)-specific phosphodiesterase gene that confers hormone and cAMP inducibility. Mol Endocrinol 11: 839–850PubMedCrossRefGoogle Scholar
  117. 117.
    McCauley L, Koh A, Beecher C, Rosol T (1997) Proto-oncogene c-fos is transcriptionally regulated by parathyroid hormone (PTH) and PTH-related protein in a cyclic adenosine monophosphate-dependent manner in osteoblastic cells. Endocrinology 138: 5427–5433PubMedCrossRefGoogle Scholar
  118. 118.
    Li X, Hales K, Watanabe G, Lee R, Pestell R, Hales D (1997) The effect of tumor necrosis factor alpha and cAMP on induction of AP-1 activity in MA-10 tumor Leydig cells. Endocrine 6: 317–324PubMedCrossRefGoogle Scholar
  119. 119.
    Zhou J, Wright P, Wong E, Katayoun J, Morand J, Carlson D (1997) Cyclic AMP regulation of mouse proline-rich protein gene expression: isoproterenol induction of AP-1 transcription factors in parotid glands. Arch Biochem Biophys 338: 97–103PubMedCrossRefGoogle Scholar
  120. 120.
    Seybold J, Newton R, Wright L, Finney P, Giembycz M, Adcock I, Suttorp N, Barnes P (1997) Gene regulation of cAMP-specific phosphodiesterase IV isoforms and splice variants in human T-lymphocytes. Evidence for desensitization to β-agonists by PDE-induction. Am J Resp Crit Car Med 155: A692Google Scholar
  121. 121.
    Giembycz M (1996) Phosphodiesterase IV and tolerance to beta 2-adrenoceptor agonists in asthma. Trends Pharmacol Sci 17: 331–336PubMedCrossRefGoogle Scholar
  122. 122.
    Bochert G, Bartel S, Beyerdorfer I, Kuttner I, Szekeres L, Krause E (1994) Long lasting anti-adrenergic effect of 7-oxo-prostacyclin in the heart: a cycloheximide sensitive increase of phosphodiesterase isoform I and IV activities. Mol Cell Biochem 132: 57–67CrossRefGoogle Scholar
  123. 123.
    Kostic M, Erdogan S, Rena G, Borchert G, Hoch B, Bartel S, Scotland G, Huston E, Houslay M, Krause E (1997) Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxo-prostacyclin-preconditioned rat heart. J Mol Cell Cardiol 29: 3135–3146PubMedCrossRefGoogle Scholar
  124. 124.
    Ye X, Conti M, Houslay M, Farooqui S, Chen M, O’Donnell J (1997) Noradrenergic activity differentially regulates the expression of rolipram-sensitive, high affinity cyclic AMP phosphodiesterase (PDE4) in rat brain. J Neurochem 69: 2397–2404PubMedCrossRefGoogle Scholar
  125. 125.
    Sette C, Iona S, Conti M (1994) The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. J Biol Chem 269: 9245–9252PubMedGoogle Scholar
  126. 126.
    Imai A, Nashida T, Shimomuro H (1995) Regulation of cAMP phosphodiesterases by cyclic nucleotides in rat parotid gland. Biochem Mol Biol Int 37: 1029–1036PubMedGoogle Scholar
  127. 127.
    Ahlstrom M, Lamberg-Allardt C (1997) Rapid protein kinase A-mediated activation of cyclic AMP-phosphodiesterase by parathyroid hormone in UMR-106 osteoblast-like cells. J Bone Miner Res 12: 172–178PubMedCrossRefGoogle Scholar
  128. 128.
    Madelian V, La Vigne E (1996) Rapid regulation of a cyclic AMP-specific phosphodiesterase (PDE IV) by forskolin and isoproterenol in LRM55 astroglial cells. Biochem Pharmacol 51: 1739–1747PubMedCrossRefGoogle Scholar
  129. 129.
    Ekholm D, Beifrage P, Manganiello V, Degerman E (1997) Protein kinase A-dependent activation of PDE4 (cAMP-specific cyclic nucleotide phosphodiesterase) in cultured bovine vascular smooth muscle cells. Biochim Biophys Acta 1356: 64–70PubMedCrossRefGoogle Scholar
  130. 130.
    Nemoz G, Sette C, Conti M (1997) Selective activation of rolipram sensitive, cAMP-specific phosphodiesterase isoforms by phosphatidic acid. Mol Pharmacol 51: 242–249PubMedGoogle Scholar
  131. 131.
    El Bawab S, Macovschi O, Sette C, Conti M, Lagarde M, Nemoz G, Prigent A (1997) Selective stimulation of a cAMP-specific phosphodiesterase (PDE4A5) isoform by phosphatidic acid molecular species endogenously formed in rat thymocytes. Eur J Biochem 247: 1151–1157CrossRefGoogle Scholar
  132. 132.
    Barnette M, Christensen S, Essayan D, Grous M, Prabhakar U, Rush J, Kagey-Sobotka A, Torphy T (1998) SB207499 (ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. J Pharmacol Exp Ther 284: 420–426PubMedGoogle Scholar
  133. 133.
    Cohan V, Showell J, Fisher D, Pazoles C, Watson J, Turner C, Cheng J (1996) In vitro pharmacology of the novel phosphodiesterase type 4 inhibitor, CP-80633. J Pharmacol Exp Ther 278: 1356–1361PubMedGoogle Scholar
  134. 134.
    Holbrook M, Gozzard N, James T, Higgs G, Hughes B (1996) Inhibition of bronchospasm and ozone-induced airway hyperresponsiveness in the guinea-pig by CDP840, a novel phosphodiesterase type 4 inhibitor. Br J Pharmacol 118: 1192–1200PubMedCrossRefGoogle Scholar
  135. 135.
    Gozzard N, El-Hashim A, Herd C, Blake S, Holbrook M, Hughes B, Higgs G, Page C (1996) Effect of glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen induced airway responses in neonatally immunised rabbits. Br J Pharmacol 118 1201–1208PubMedCrossRefGoogle Scholar
  136. 136.
    Hughes B, Howat D, Lisle H, Holbrook M, James T, Gozzard N, Blease K, Hughes P, Kingaby R, Warrellow G et al. (1996) The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4. BrJ Pharmacol 118: 1183–1191CrossRefGoogle Scholar
  137. 137.
    Harbinson P, MacLeod D, Hawksworth R, Otoole S, Sullivan P, Heath P, Kilfeather S, Page C, Costello J, Holgate S, Lee T (1997) The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 10: 1008–1014PubMedCrossRefGoogle Scholar
  138. 138.
    Cheng J, Watson J, Pazoles C, Eskra J, Griffiths R, Cohan V, Turner C, Showell H, Pettipher E (1997) The phosphodiesterase type 4 (PDE4) inhibitor CP-80, 633 elevates plasma cyclic AMP levels and decreases tumor necrosis factor-alpha (TNFalpha) production in mice: effect of adrenalectomy. J Pharmacol Exp Ther 280: 621–626PubMedGoogle Scholar
  139. 139.
    Karlsson J, Aldous D (1997) Phosphodiesterase 4 inhibitors for the treatment of asthma. Exp Opin Ther Patents 7: 989–1003CrossRefGoogle Scholar
  140. 140.
    Tenor H, Shute J, Church M, Hatzelmann A, Schudt C (1995) Inhibition of human peripheral blood eosinophil LTC4 production by PDE inhibitors. Eur Res J 8 (Supp 9): 152Google Scholar
  141. 141.
    Raeburn D, Underwood S, Lewis S, Woodman V, Battram C, Tomkinson A, Sharma S, Jordan R, Souness J, Webber S et al (1994) Anti-inflammatory and bronchodilator properties of RP73401, a novel and selective phosphodiesterase type IV inhibitor. Br J Pharmacol 133: 1423–1431CrossRefGoogle Scholar
  142. 142.
    Packer M, Carver J, Rodeheffer R, Ivanhoe R, DiBianco R, Zeldis S, Hendrix G, Bommer W, Elkayam U, Kukin M et al (1991) Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research group. N Engl J Med 325: 1468–1475PubMedCrossRefGoogle Scholar
  143. 143.
    Colucci W, Sonnenblick E, Adams K, Berk M, Brozena S, Cowley A, Grabicki J, Kubo S, LeJemtel T, Littler W et al (1993) Efficacy of phosphodiesterase inhibition with milrinone in combination with converting enzyme inhibitors in patients with heart failure. The Milrinone Multicenter Trials Investigators. J Am Coll Cardiol 22: 113A–118APubMedCrossRefGoogle Scholar
  144. 144.
    Cowley A, Skene A (1994) Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Br Heart J 72: 226–230PubMedCrossRefGoogle Scholar
  145. 145.
    Degerman E, Beifrage P, Manganiello V (1997) Structure, localization and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem 272: 6823–6826PubMedCrossRefGoogle Scholar
  146. 146.
    Sheth SB, Chaganti K, Bastepe M, Ajuria J, Brennan K, Biradavolu R, Colman R (1997) Cyclic AMP phosphodiesterases in human lymphocytes. Br J Haematol 9: 784–789CrossRefGoogle Scholar
  147. 147.
    Tang K, Jang E, Haslam R (1997) Expression and mutagenesis of the catalytic domain of cGMP-inhibited phosphodiesterase (PDE3) cloned from human platelets. Biochem J 323: 217–224PubMedGoogle Scholar
  148. 148.
    Komas N, Movsesian M, Kedev S, Degerman E, Belfrage P, Manganiello C (1996) cGMP-inhibited phosphodiesterases (PDE3). In: C Schudt, G Dent, KF Rabe (eds): Phosphodiesterase inhibitors. Academic Press, San Diego, 89–109CrossRefGoogle Scholar
  149. 149.
    Kasuya J, Goko H, Fujita-Yamaguchi Y (1995) Multiple transcripts for the human cardiac form of the cGMP-inhibited cAMP phosphodiesterase. J Biol Chem 270: 14305–14312PubMedCrossRefGoogle Scholar
  150. 150.
    Rahn T, Ronnstrand L, Leroy M, Wernstedt C, Tornquist H, Manganiello V, Belfrage P, Degerman E (1996) Identification of the site in the cGMP-inhibited phosphodiesterase phosphorylated in adipocytes in response to insulin and isoproterenol. J Biol Chem 271: 11575–11580PubMedCrossRefGoogle Scholar
  151. 151.
    Wagner R, Smith C, Taylor A, Rhoades R (1997) Phosphodiesterase inhibition improves agonist-induced relaxation of hypertensive pulmonary arteries. J Pharmacol Exp Ther 282: 1650–1657PubMedGoogle Scholar
  152. 152.
    Rabe K, Tenor H, Dent G, Schudt C, Liebig S, Magnussen H (1993) Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization. Am J Physiol 264: L458–L464PubMedGoogle Scholar
  153. 153.
    Fujimura M, Kamio Y, Myou S, Hashimoto T, Matsuda T (1997) Effect of a phosphodiesterase 3 inhibitor, cilostazol, on bronchial hyperresponsiveness in elderly patients with asthma. Int Arch Allergy Immunol 114: 379–384PubMedCrossRefGoogle Scholar
  154. 154.
    Robicsek S, Blanchard D, Djeu Y, Krzanowski J, Szentivanyi A, Poison J (1991) Multiple high affinity cAMP-phosphodiesterases in human T-lymphocytes. Biochem Pharmacol 42: 869–877PubMedCrossRefGoogle Scholar
  155. 155.
    Tenor H, Stanciu L, Schudt C, Hatzelmann A, Wendel A, Djukanovic R, Church M, Shute J (1995) Cyclic nucleotide phosphodiesterases from purified human CD4+ and CD8+ T-lymphocytes. Clin Exp Allergy 25: 616–624PubMedCrossRefGoogle Scholar
  156. 156.
    Schudt C, Tenor H, Loos U, Mallmann P, Szamel M, Resch K (1993) Effect of selective phosphodiesterase (PDE) inhibitors on activation of human macrophages and lymphocytes. Eur Resp J 6: 367SGoogle Scholar
  157. 157.
    Pan X, Arauz E, Krzanowski J, Fitzpatrick D, Poison J (1994) Synergistic interactions between selective pharmalogical inhibitors of phosphodiesterase isoenzyme families PDE III and PDE IV to attenuate proliferation of rat vascular smooth muscle cells. Biochem Pharmacol 48: 827–835PubMedCrossRefGoogle Scholar
  158. 158.
    Rabe K, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H (1994) Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 266: L536–L543PubMedGoogle Scholar
  159. 159.
    Schudt C, Winder S, Forderkunz S, Hatzelmann A, Ullrich V (1991) Influcence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Ca. Naunyn-Schmiedebergs Arch Pharmacol 344: 682–690PubMedGoogle Scholar
  160. 160.
    Kilian U, Beume R, Eltze M, Schudt C (1989) Is phosphodiesterase inhibition a relevant bronchospasmolytic principle? Agents Actions 28: 331–348Google Scholar
  161. 161.
    Hoymann H, Heinrich U, Beume R, Kilian U (1994) Comparative investigation of the effects of zardaverine and theophylline on pulmonary functions in rats. Exp Lung Res 20: 235–250PubMedCrossRefGoogle Scholar
  162. 162.
    Hatzelmann A, Engelstätter R, Morley J, Mazzoni L (1996) Enzymatic and functional aspects of dual-selective PDE3/4 inhibitors. In: C Schudt, G Dent, KF Rabe (eds): Phosphodiesterase inhibitors. Academic Press, San Diego, 147–160CrossRefGoogle Scholar
  163. 163.
    Suttorp N, Ehreiser P, Hippenstiel S, Fuhrmann M, Krull M, Tenor H, Schudt C (1996) Hypermeability of pulmonary endothelial monolayer: protective role of phosphodiesterase isoenzymes 3 and 4. Lung 174: 181–194PubMedGoogle Scholar
  164. 164.
    Suttorp N, Weber U, Welsch T, Schudt C (1993) Role of phosphodiesterases in the regulation of endothelial permeability in vitro. J Clin Invest 9: 1421–1428CrossRefGoogle Scholar
  165. 165.
    Houslay M, Milligan G (1997) Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem Sci 22: 217–224PubMedCrossRefGoogle Scholar
  166. 166.
    Underwood DC, Matthews JK, Osborn RR, Bochnowicz S, Torphy TJ (1997) The influence of endogeneous catecholamines on the inhibitory effects of rolipram against early-and late-phase response to antigen in the guinea pig. J Pharmacol Exp Ther 280: 210–219PubMedGoogle Scholar
  167. 167.
    Iannone M, Wolberg G, Zimmermann T (1989) Chemotactic peptide induces cAMP elevation in human neutrophils by amplification of the adenylate cyclase response to endogenously produced adenosine. J Biol Chem 264: 20177–20180PubMedGoogle Scholar
  168. 168.
    Uhlig S, Featherstone R, Held H, Nusing R, Schudt C, Wendel A (1997) Attenuation by phosphodiesterase inhibitors of lipopolysaccharide-induced thromboxane release and bronchochonstriction in rat lungs. J Pharmacol Exp Ther 282: 1453–1459Google Scholar
  169. 169.
    Seeger W, Hansen T, Rossig R, Schmehl T, Schutte H, Kramer HJ, Walmrath D, Weissmann N, Grimminger F, Suttorp N (1995) Hydrogen peroxide-induced increase in lung endothelial and epithelial permeability-effect of adenylate cyclase stimulation and phosphodiesterase inhibition. Microvasc Res 50: 1–17PubMedCrossRefGoogle Scholar
  170. 170.
    Schudt C, Winder S, Eltze M, Kilian U, Beume R (1991). Zardaverine: a cyclic AMP specific PDE III/IV inhibitor. Agents Actions (Suppl) 34: 379–402Google Scholar
  171. 171.
    Underwood D, Kotzer C, Bochnowitz S, Osbom R, Luttmann M, Hay D, Torphy T (1994) Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther 270: 250–259PubMedGoogle Scholar
  172. 172.
    Banner, K, Page C (1995) Acute versus chronic administration of phosphodiesterase inhibitors on allergen-induced pulmonary cell influx in sensitized guinea-pigs. Br J Pharmacol 114: 93–98PubMedCrossRefGoogle Scholar
  173. 173.
    Fischer, W, Schudt C, Wendel A (1993) Protection by phosphodiesterase inhibitors against endotoxin-induced liver injury in galactosamine-sensitized mice. Biochem Pharmacol 45: 2399–2404PubMedCrossRefGoogle Scholar
  174. 174.
    Brunnee T, Engelstätter R, Steinijans V, Kunkel G (1992) Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur J Respir 5: 982–985Google Scholar
  175. 175.
    Jordan K, Fischer J, Engelstätter R, Steinijans V (1993) Einfluß eines inhalierbaren selektiven Phosphodiesterase-Hemmers (PDEIII/IV-Hemmer Zardaverin) auf die Lungenfunktion von Patienten mit Asthma bronchiale. Atemw-Lungenkrkh 19: 358–359Google Scholar
  176. 176.
    Wempe J, Postma D, Diupmans J, Koeter G (1992) Bronchodilating Effect of zardaverine, a selective phosphodiesterase III/IV inhibitor. Eur Resp J 5: 213sGoogle Scholar
  177. 177.
    Schudt C, Tenor H, Wendel A, Eltze M, Magnussen H, Rabe H (1993) Influence of PDE III/IV inhibitor B9004-070 on contraction and PDE activities in airway and vascular smooth muscle. Am Rev Respir Dis 147, A183Google Scholar
  178. 178.
    Beume R, Kilian U, Brand U, Haefner D, Eltze M, Flockerzi D (1993) The bronchospasmolytic effect of the PDE III/IV inhibitors B9004-070 and zardaverine-dependency on the route of administration in guinea pigs. Am Rev Resp Dis 147, A184Google Scholar

Copyright information

© Springer Basel AG 1999

Authors and Affiliations

  • Hermann Tenor
    • 1
  • Christian Schudt
    • 1
  1. 1.Byk Gulden Lomberg Chemische Fabrik GmbHKonstanzGermany

Personalised recommendations