Re. Santing et al., PHOSPHODIESTERASE INHIBITORS REDUCE BRONCHIAL HYPERREACTIVITY AND AIRWAY INFLAMMATION IN UNRESTRAINED GUINEA-PIGS, European journal of pharmacology, 275(1), 1995, pp. 75-82
A new guinea pig model of allergic asthma was used to investigate the
effects of low doses of the phosphodiesterase inhibitors, rolipram (ph
osphodiesterase IV selective), ORG 20241 -(3,4-dimethoxyphenyl)-thiazo
le-2-carboximidamide; dual phosphodiesterase III/IV inhibitor with som
e selectivity for the phosphodiesterase IV isoenzyme), and of theophyl
line (non-selective) on allergen-induced early and late phase asthmati
c reactions, bronchial hyperreactivity to histamine inhalation, and ai
rway inflammation. Theophylline (25 mg/kg i.p.) and ORG 20241 (5 mg/kg
i.p.) did not affect histamine-induced bronchoconstriction, whereas r
olipram (75 mu g/kg i.p.) only slightly reduced the response to histam
ine at 7 h after administration. However, bronchial hyperreactivity af
ter the early and after the late reaction was significantly reduced by
theophylline, rolipram and ORG 20241, while bronchoalveolar lavage st
udies revealed a selective inhibition of airway inflammation by the ph
osphodiesterase inhibitors. Theophylline significantly reduced the num
ber of eosinophils, neutrophils and macrophages; rolipram reduced the
number of neutrophils and lymphocytes, and ORG 20241, the number of eo
sinophils and macrophages. None of the compounds at the dosage indicat
ed reduced the early and late reaction when administered i.p. 1 h befo
re allergen exposure to defined dual responding animals. These results
indicate that non-bronchodilator doses of these phosphodiesterase inh
ibitors markedly reduce the allergen-induced development of bronchial
hyperreactivity as well as airway inflammation, presumably by selectiv
ely inhibiting cellular migration. The results suggest that an orchest
rated series of cellular interactions is involved in the development o
f bronchial hyperreactivity. It is concluded that phosphodiesterase in
hibitors may be very useful in the treatment of bronchial asthma.