EFFECTS OF INHIBITORS OF PHOSPHODIESTERASE, ON ANTIGEN-INDUCED BRONCHIAL HYPERREACTIVITY IN CONSCIOUS SENSITIZED GUINEA-PIGS AND AIRWAY LEUKOCYTE INFILTRATION

1 The aim of this study was to determine the effects of inhibitors of phosphodiesterase (PDE) on the early and late phase bronchoconstrictio n in sensitized, conscious guinea-pigs and the subsequent development of acute airway hyperreactivity to the inhaled thromboxane mimetic, U4 6619, and leukocyte infiltration following ovalbumin (OvA) challenge. 2 Following an inhalation challenge with OvA, there was an early bronc hoconstriction which peaked at 15 min with recovery after 3-4 h. A lat e phase bronchoconstriction occurred between 17 and 24 h after challen ge. The PDE 4 inhibitors, Ro 20-1724 (3 mg kg(-1), i.p.) and rolipram (1 mg kg(-1), i.p.) administered 30 min before and 6 h after antigen c hallenge (double dosing regimen), did not affect the development of th e early or late phase responses. 3 Seventeen to twenty four hours foll owing an acute OvA or saline challenge, a consistently greater broncho constrictor response to inhaled U46619 was observed in the OvA challen ged group. This increase in responsiveness was significantly attenuate d by the administration of Ro 20-1724 and rolipram 30 min before and 6 h after antigen challenge (P<0.05); this was not attributable to a re sidual bronchodilator effect of these compounds. There was a trend tow ards inhibition of the hyperreactivity to U46619 by aminophylline but not by the PDE3 inhibitors, siguazodan or SKF 95654. 4 Aminophylline, rolipram and Ro 20-1724 when administered as the double dose regimen a ttenuated the rise in macrophages, eosinophils and neutrophils recover ed in bronchial lavage fluid 17 to 24 h after antigen challenge. 5 The dose of Ro 20-1724 given at 6 h post challenge was essential for atte nuation of airway hyperreactivity and to protect against leukocyte inf lux. 6 In summary, aminophylline, rolipram and Ro 20-1724 have anti-in flammatory effects against antigen-induced airway leukocyte infiltrati on. Rolipram and Ro 20-1724 additionally attentuated the development o f acute airway hyperreactivity, effects which are probably mediated th rough inhibition of PDE type 4. A dose of PDE inhibitor 6 h after the antigen challenge appears to be essential to achieve this protection. Inhibitors of PDE type 3 were generally without effect. However, there was no effect of rolipram or Ro 20-1724 on the development of either the early or late phase type responses.