ISBUFYLLINE, A NEW XANTHINE DERIVATIVE, INHIBITS AIRWAY HYPERRESPONSIVENESS AND AIRWAY INFLAMMATION IN GUINEA-PIGS

The pharmacological actions of the new xanthine, isbufylline, were eva luated in several models of airway hyperresponsiveness and airway infl ammation in guinea pigs. At a dose (106 mu mol kg(-1) i.p.) providing complete protection against acetylcholine aerosol-induced dyspnea in t he guinea pig, isbufylline inhibited platelet activating factor (PAF)- and antigen-induced eosinophil infiltration into bronchoalveolar lava ge fluid 24 h after challenge of normal and actively immunized guinea pigs, respectively. In addition, this dose of isbufylline also inhibit ed capsaicin-induced extravasation of protein into bronchoalveolar lav age fluid. Isbufylline, 4.2 mu mol kg(-1) i.v., significantly inhibite d PAF-induced bronchial hyper-responsiveness to i.v. histamine, withou t exerting evident bronchodilator activity. On the other hand the bron chodilator, salbutamol, at a dose (10.4 mu mol kg(-1) i.p.) shown to b e equieffective to isbufylline (106 mu mol kg(-1) i.p.) for blocking a cetylcholine aerosol-induced dyspnea, had no protective action against PAF- or antigen-induced eosinophil recruitment in bronchoalveolar lav age fluid, or against capsaicin-induced plasma protein extravasation. Furthermore, salbutamol (3.5 mu mol kg(-1)) significantly potentiated allergen-induced cell infiltration and PAF-induced bronchial hyperresp onsiveness. The results suggest that isbufylline can exert significant anti-inflammatory actions in guinea pig airways, in addition to its b ronchodilator activity. These pharmacological activities are not share d by the beta(2)-adrenoceptor agonist, salbutamol.