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. 1993 Feb;108(2):562–568. doi: 10.1111/j.1476-5381.1993.tb12841.x

Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus.

J Cortijo 1, J Bou 1, J Beleta 1, I Cardelús 1, J Llenas 1, E Morcillo 1, R W Gristwood 1
PMCID: PMC1907986  PMID: 8383567

Abstract

1. We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDE IV) in the relaxation of human bronchus and guinea-pig trachea in vitro and in guinea-pigs in vivo. 2. Functional studies showed that the selective PDE IV inhibitors, rolipram and denbufylline, relaxed human and guinea-pig preparations in vitro. 3. Two clinically used xanthine non-selective PDE inhibitors, theophylline and pentoxifylline, were also effective in these preparations, but were much less potent than the selective agents used. 4. The rank order of potency for the four PDE inhibitors in both species was similar. 5. Biochemical studies indicated that PDE IV was the major PDE isoform present in the human bronchial tissue. PDEs I, II and V were also identified. 6. Theophylline and pentoxifylline were, as expected, non-selective inhibitors of the human enzymes, but there was a good correlation between PDE IV inhibitory and bronchorelaxation potencies, suggesting that PDE IV inhibition is important for the clinical bronchodilator activities of the two xanthine compounds. 7. We have confirmed the ability of selective PDE IV inhibitors to cause bronchodilatation in guinea-pigs in vivo. 8. We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic.

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Selected References

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  1. Bryson S. E., Rodger I. W. Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle. Br J Pharmacol. 1987 Nov;92(3):673–681. doi: 10.1111/j.1476-5381.1987.tb11371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cortijo J., Sarriá B., Pedrós C., Perpiñ M., Paris F., Morcillo E. The relaxant effects of cromakalim (BRL 34915) on human isolated airway smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 1992 Oct;346(4):462–468. doi: 10.1007/BF00171091. [DOI] [PubMed] [Google Scholar]
  3. Downing S. J., Hollingsworth M. One way cross tolerance between cromakalim and salbutamol in the uterus of the rat in vivo. Br J Pharmacol. 1992 Jan;105(1):129–134. doi: 10.1111/j.1476-5381.1992.tb14223.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Feth F., Rascher W., Michel M. C. Neuropeptide Y (NPY) receptors in HEL cells: comparison of binding and functional parameters for full and partial agonists and a non-peptide antagonist. Br J Pharmacol. 1992 Jan;105(1):71–76. doi: 10.1111/j.1476-5381.1992.tb14212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Giembycz M. A., Dent G. Prospects for selective cyclic nucleotide phosphodiesterase inhibitors in the treatment of bronchial asthma. Clin Exp Allergy. 1992 Mar;22(3):337–344. doi: 10.1111/j.1365-2222.1992.tb03095.x. [DOI] [PubMed] [Google Scholar]
  6. Gristwood R. W., Beleta J., Bou J., Cardelús I., Fernández A. G., Llenas J., Berga P. Studies on the cardiac actions of flosequinan in vitro. Br J Pharmacol. 1992 Apr;105(4):985–991. doi: 10.1111/j.1476-5381.1992.tb09089.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gristwood R. W., Eden R. J., Owen D. A., Taylor E. M. Pharmacological studies with SK&F 94120, a novel positive inotropic agent with vasodilator activity. J Pharm Pharmacol. 1986 Jun;38(6):452–459. doi: 10.1111/j.2042-7158.1986.tb04609.x. [DOI] [PubMed] [Google Scholar]
  8. Gristwood R. W., Llupiá J., Fernández A. G., Berga P. Effects of theophylline compared with prednisolone on late phase airway leukocyte infiltration in guinea pigs. Int Arch Allergy Appl Immunol. 1991;94(1-4):293–294. doi: 10.1159/000235388. [DOI] [PubMed] [Google Scholar]
  9. Livi G. P., Kmetz P., McHale M. M., Cieslinski L. B., Sathe G. M., Taylor D. P., Davis R. L., Torphy T. J., Balcarek J. M. Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase. Mol Cell Biol. 1990 Jun;10(6):2678–2686. doi: 10.1128/mcb.10.6.2678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Nicholson C. D., Challiss R. A., Shahid M. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci. 1991 Jan;12(1):19–27. doi: 10.1016/0165-6147(91)90484-a. [DOI] [PubMed] [Google Scholar]
  11. Nicholson C. D., Jackman S. A., Wilke R. The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re-uptake site. Br J Pharmacol. 1989 Jul;97(3):889–897. doi: 10.1111/j.1476-5381.1989.tb12029.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Nolte D. Lungenfunktionsuntersuchungen zur bronchospasmolytischen Wirkung von 3,7-Dimethyl-1-(5-oxo-hexyl)-xanthin. Arzneimittelforschung. 1971 Oct;21(10):1453–1456. [PubMed] [Google Scholar]
  13. Persson C. G. Overview of effects of theophylline. J Allergy Clin Immunol. 1986 Oct;78(4 Pt 2):780–787. doi: 10.1016/0091-6749(86)90061-8. [DOI] [PubMed] [Google Scholar]
  14. Reeves M. L., Leigh B. K., England P. J. 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. 1987 Jan 15;241(2):535–541. doi: 10.1042/bj2410535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Silver P. J., Hamel L. T., Perrone M. H., Bentley R. G., Bushover C. R., Evans D. B. Differential pharmacologic sensitivity of cyclic nucleotide phosphodiesterase isozymes isolated from cardiac muscle, arterial and airway smooth muscle. Eur J Pharmacol. 1988 May 20;150(1-2):85–94. doi: 10.1016/0014-2999(88)90753-4. [DOI] [PubMed] [Google Scholar]
  16. Takagi K., Ogawa K., Tanaka H., Satake T., Watanabe Y., Chijiwa T., Hidaka H. Relaxant effects of various xanthine derivatives. Relationship to cyclic nucleotide phosphodiesterase inhibition. Adv Second Messenger Phosphoprotein Res. 1992;25:353–362. [PubMed] [Google Scholar]
  17. Torphy T. J., Undem B. J. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax. 1991 Jul;46(7):512–523. doi: 10.1136/thx.46.7.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ward A., Clissold S. P. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987 Jul;34(1):50–97. doi: 10.2165/00003495-198734010-00003. [DOI] [PubMed] [Google Scholar]

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