Skip to main content
NCBI home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 1999;8(3):153–157. doi: 10.1080/09629359990487

Reduced airway hyperresponsiveness by phosphodiesterase 3 and 4 inhibitors in guinea-pigs.

N Germain 1, E Boichot 1, J M Planquois 1, V Lagente 1
PMCID: PMC1781799  PMID: 10704053

Abstract

The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48h after OA, a significant reduction (P<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (P<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Full Text

The Full Text of this article is available as a PDF (163.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Banner K. H., Page C. P. Theophylline and selective phosphodiesterase inhibitors as anti-inflammatory drugs in the treatment of bronchial asthma. Eur Respir J. 1995 Jun;8(6):996–1000. [PubMed] [Google Scholar]
  2. Bardin P. G., Dorward M. A., Lampe F. C., Franke B., Holgate S. T. Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol. 1998 Apr;45(4):387–391. doi: 10.1046/j.1365-2125.1998.t01-1-00689.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beavo J. A., Conti M., Heaslip R. J. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol. 1994 Sep;46(3):399–405. [PubMed] [Google Scholar]
  4. Boichot E., Lagente V., Carre C., Waltmann P., Mencia-Huerta J. M., Braquet P. Bronchial hyperresponsiveness and cellular infiltration in the lung of guinea-pigs sensitized and challenged by aerosol. Clin Exp Allergy. 1991 Jan;21(1):67–76. doi: 10.1111/j.1365-2222.1991.tb00806.x. [DOI] [PubMed] [Google Scholar]
  5. Boichot E., Lagente V., Paubert-Braquet M., Frossard N. Inhaled substance P induces activation of alveolar macrophages and increases airway responses in the guinea-pig. Neuropeptides. 1993 Nov;25(5):307–313. doi: 10.1016/0143-4179(93)90048-f. [DOI] [PubMed] [Google Scholar]
  6. Danahay H., Broadley K. J. Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration. Br J Pharmacol. 1997 Jan;120(2):289–297. doi: 10.1038/sj.bjp.0700901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fujimura M., Kamio Y., Myou S., Hashimoto T., Matsuda T. Effect of a phosphodiesterase 3 inhibitor, cilostazol, on bronchial hyperresponsiveness in elderly patients with asthma. Int Arch Allergy Immunol. 1997 Dec;114(4):379–384. doi: 10.1159/000237698. [DOI] [PubMed] [Google Scholar]
  8. Gantner F., Kupferschmidt R., Schudt C., Wendel A., Hatzelmann A. In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-alpha release by PDE inhibitors. Br J Pharmacol. 1997 May;121(2):221–231. doi: 10.1038/sj.bjp.0701124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Germain N., Bertin B., Legendre A., Martin B., Lagente V., Payne A., Boichot E. Selective phosphodiesterase inhibitors modulate the activity of alveolar macrophages from sensitized guinea-pigs. Eur Respir J. 1998 Dec;12(6):1334–1339. doi: 10.1183/09031936.98.12061334. [DOI] [PubMed] [Google Scholar]
  10. Holbrook M., Gozzard N., James T., Higgs G., Hughes B. Inhibition of bronchospasm and ozone-induced airway hyperresponsiveness in the guinea-pig by CDP840, a novel phosphodiesterase type 4 inhibitor. Br J Pharmacol. 1996 Jul;118(5):1192–1200. doi: 10.1111/j.1476-5381.1996.tb15523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Holgate S. T., Djukanovic R., Wilson J., Roche W., Howarth P. H. Inflammatory processes and bronchial hyperresponsiveness. Clin Exp Allergy. 1991 Jan;21 (Suppl 1):30–36. doi: 10.1111/j.1365-2222.1991.tb01703.x. [DOI] [PubMed] [Google Scholar]
  12. Howell R. E., Sickels B. D., Woeppel S. L. Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. J Pharmacol Exp Ther. 1993 Feb;264(2):609–615. [PubMed] [Google Scholar]
  13. Lagente V., Moodley I., Perrin S., Mottin G., Junien J. L. Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung. Eur J Pharmacol. 1994 Apr 1;255(1-3):253–256. doi: 10.1016/0014-2999(94)90107-4. [DOI] [PubMed] [Google Scholar]
  14. Lagente V., Pruniaux M. P., Junien J. L., Moodley I. Modulation of cytokine-induced eosinophil infiltration by phosphodiesterase inhibitors. Am J Respir Crit Care Med. 1995 Jun;151(6):1720–1724. doi: 10.1164/ajrccm.151.6.7539326. [DOI] [PubMed] [Google Scholar]
  15. Ortiz J. L., Vallés J. M., Martí-Cabrera M., Cortijo J., Morcillo E. J. Effects of selective phosphodiesterase inhibitors on platelet-activating factor- and antigen-induced airway hyperreactivity, eosinophil accumulation, and microvascular leakage in guinea pigs. Naunyn Schmiedebergs Arch Pharmacol. 1996 Jan;353(2):200–206. doi: 10.1007/BF00168758. [DOI] [PubMed] [Google Scholar]
  16. Planquois J. M., Ruffin-Morin Y., Lagente V., Payne A. N., Dahl S. G. Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea. Fundam Clin Pharmacol. 1996;10(4):356–367. doi: 10.1111/j.1472-8206.1996.tb00587.x. [DOI] [PubMed] [Google Scholar]
  17. Rabe K. F., Tenor H., Dent G., Schudt C., Liebig S., Magnussen H. Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization. Am J Physiol. 1993 May;264(5 Pt 1):L458–L464. doi: 10.1152/ajplung.1993.264.5.L458. [DOI] [PubMed] [Google Scholar]
  18. Spina D., Harrison S., Page C. P. Regulation by phosphodiesterase isoenzymes of non-adrenergic non-cholinergic contraction in guinea-pig isolated main bronchus. Br J Pharmacol. 1995 Oct;116(4):2334–2340. doi: 10.1111/j.1476-5381.1995.tb15074.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Teixeira M. M., Gristwood R. W., Cooper N., Hellewell P. G. Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs of the future? Trends Pharmacol Sci. 1997 May;18(5):164–171. doi: 10.1016/s0165-6147(97)01049-3. [DOI] [PubMed] [Google Scholar]
  20. Tonnel A. B., Joseph M., Gosset P., Fournier E., Capron A. Stimulation of alveolar macrophages in asthmatic patients after local provocation test. Lancet. 1983 Jun 25;1(8339):1406–1408. doi: 10.1016/s0140-6736(83)92356-5. [DOI] [PubMed] [Google Scholar]
  21. Torphy T. J. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998 Feb;157(2):351–370. doi: 10.1164/ajrccm.157.2.9708012. [DOI] [PubMed] [Google Scholar]
  22. Uno T., Tanaka H., Nagai H. Effects of isoenzyme selective phosphodiesterase inhibitors on bacterial lipopolysaccharide-induced bronchial hyperreactivity in guinea pigs. Gen Pharmacol. 1998 Feb;30(2):167–173. doi: 10.1016/s0306-3623(97)00102-x. [DOI] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES