Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram

D. C. Underwood, R. R. Osborn, L. B. Novak, J. K. Matthews, S. J. Newsholme, B. J. Undem, J. M. Hand, T. J. Torphy

Research output: Contribution to journalArticlepeer-review

Abstract

Selective inhibition of the low K(m) cyclic AMP-specific phosphodiesterase has been shown to inhibit inflammatory cell function and relax airway smooth muscle. These studies were conducted to characterize the bronchodilator and anti-inflammatory activity of rolipram, an archetypical cyclic AMP-specific phosphodiesterase inhibitor, in in vitro and in vivo guinea pig airway models. In isolated tracheal rings from ovalbumin (OA)-sensitive guinea pigs, both R- and S-enantiomers of rolipram (1 μM) significantly antagonized OA- induced contractions. In contrast, neither enantiomer at concentrations up to 1 μM significantly inhibited histamine- or LTD4-induced contractions. In superfusion and mediator release experiments, both enantiomers of rolipram significantly reduced antigen-induced prostaglandin D2 release, but had minimal effect on histamine release. In anesthetized, ventilated OA-sensitive guinea pigs, racemic rolipram or enantiomers reduced OA-induced bronchoconstriction with ID50 values of approximately 0.25 mg/kg i.v. Histamine- and leukotriene D4-induced bronchoconstriction were not affected by doses of rolipram which abolished the response to OA. Higher doses (3-10 mg/kg) reduced histamine-, but not the leukotriene D4-induced bronchoconstriction. In conscious OA-sensitive guinea pigs, intragastric pretreatment with rolipram dose-dependently reduced both the OA-induced decreases in specific conductance as well as the corresponding pulmonary eosinophil influx as assessed by both bronchoalveolar lavage and histological evaluation. Therefore, rolipram produces significant inhibition of antigen- induced bronchoconstrictor and inflammatory responses, thus providing strong evidence that this pharmacological approach may be of significant therapeutic value in allergic asthma. Rolipram's minimal activity against exogenous spasmogen-induced airway constriction suggests that inhibition of mast cell degranulation, rather than direct bronchodilator activity, may be the primary mechanism by which rolipram inhibits antigen-induced bronchoconstriction.

Original languageEnglish (US)
Pages (from-to)306-313
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume266
Issue number1
StatePublished - 1993
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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