PHOSPHODIESTERASE INHIBITORS REDUCE BRONCHIAL HYPERREACTIVITY AND AIRWAY INFLAMMATION IN UNRESTRAINED GUINEA-PIGS

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.