The synergistic effect of adenosine A2A receptors agonist, type IV phosphodiestease inhibitor and ATP-sensitive K channels activation on free radicals production and aggregation of human polymorphoneuclear leukocytes

The adenosine A(2A) receptor agonist CGS21680 (50, 100 and 200 mug/ml), the phosphodiserease type IV (PDE IV) inhibitor Rolipram (50, 100 and 200 mug/ml) and, ATP-sensitive K+ channels activator Cromakalim (30 and 40 mug/ml), when added separately, inhibit oxygen free radicals production from isolated human polymorphoneuclear leukocytes (PMNLs), stimulated with phorbol myristate acetate (PMA), in a dose dependent manner. When both CGS21680 and Rolipram were combined, in vitro, the inhibitory effect on PMNLs free radicals production was synergistic. On the other hand, when both the ATP-sensitive K+ channels opener (K-ATP) Cromakalim and the type IV PDE inhibitor Rolipram were combined, produced negative synergism (the inhibitory effect of both drugs disappeared). Furthermore, CGS21680, Rolipram, Cromakalim and Forskolin produced no significant inhibitory effect on PMNLs aggregation when added separately. But when various combinations of the above drugs were used, produced significant inhibition of aggregation. Only CGS21680 exhibited a scavenging effect on free radicals production. From the above results, combination of adenosine A(2A) agonists and type IV PDE inhibitors could serve as potentially novel anti-inflammatory drugs. Furthermore, ATP-sensitive K+ channels activators should be considered for further investigation as anti-inflammatory drug. (C) 2004 Elsevier Ltd. All rights reserved.