LOCAL EXPOSURE TO SALBUTAMOL OR BT(2), CYCLIC-AMP INHIBITS PLEURAL EXUDATION AND LEUKOCYTE INFLUX CAUSED BY ANTIGEN IN RATS

The local effect of salbutamol and N-6,2'-O-dibutyryl adenosine 3':5'- cyclic monophosphate (Bt(2) cyclic AMP) on the rat pleural inflammatio n caused by allergen was investigated. Antigen (ovalbumin, 12 mu g/cav ity) intrathoracically administered to immunized rats led to a marked pleural protein extravasation and leukocyte infiltration, as attested by the quantification of protein and enumeration of leukocytes recover ed from the pleural cavity. Salbutamol (10-40 mu g/cavity) and the cel l-permeable cyclic AMP analogue, Bt(2) cyclic AMP (20-160 mu g/cavity) , injected 1 h and 5 min before the antigen, respectively, inhibited t he exudation occurring within 30 min, and neutrophil and eosinophil ac cumulation ocurring 4 and 24 h, respectively. The late eosinophilia wa s also markedly attenuated by salbutamol administered 10 min post-chal lenge, when mast cells had already been degranulated. Pretreatment wit h the beta-adrenoceptor antagonist propranolol (1 mg/kg, i.v.) failed to modify the inhibitory effect of Bt(2) cyclic AMP, but abolished the blockade caused by salbutamol of leukocyte infiltration under conditi ons where the salbutamol anti-exudatory activity was impaired to about 80%. In another set of experiments, salbutamol (20 and 40 mu g/cavity ) markedly inhibited the exudation caused by histamine and 5-hydroxytr yptamine (5-HT) which, though to a lesser extent, was also sensitive t o Bt(2) cyclic AMP (80 mu g/cavity). As observed with allergic pleuris y, propranolol impaired the inhibition by salbutamol of histamine- and 5-HT-induced exudation, whereas the Bt(2) cyclic AMP inhibition was n ot affected. We conclude that salbutamol and Bt(2) cyclic AMP share th e ability to inhibit pleural exudation and leukocyte recruitment cause d by allergen in immunized rats, suggesting that the anti-inflammatory effect of salbutamol may be mediated by a cyclic AMP signaling pathwa y, probably via beta(2)-adrenoceptor activation.