The effect of chronic caffeine treatment (9 weeks) on AR receptor function was studied in isolated tracheal strips (ITSs) of guinea pigs. Guinea pigs received drinking water containing sucrose 20 g/l with or without caffeine 600 mg/l. Serum concentration of caffeine was 39.1± 3.9 mol/l measured by HPLC. The experiments were carried out in ITSs precontracted with metacholine. In ITSs, AR exerted a concentration-dependent relaxation. Sensitivity of epithelium-intact (E+) ITSs to AR was significantly enhanced after 1 week caffeine treatment, but was gradually reverted afterwards. In epithelium-denuded (E-) preparations, the enhancement of the AR,s effects were maintained throghout the 9 weeks of caffeine treatment. In a coaxial bioassay system (E- control ITS in an E+ tracheal tube obtained from caffeine treated animals) inhibition of COX (indomethacin, diclofenac), lipooxygenase (NDGA) or mast cell degranulation (cromolyn) did not influence the AR-induced mechanical response of the E- control tissue. In contrast, capsaicine pretreatment enhanced the relaxations evoked by AR in the coaxially mounted ITS. It can be supposed that after chronic caffeine exposition, reversion of the sensitization to AR can be probably due, at least in part, to an epithelial overproduction of epithelium-derived contracting factor(s).