Abstract: After repeated treatment with isoproterenol aerosol or intramuscular injection of the drug for 5 hrs, the protective effect of isoproterenol aerosol against histamineinduced asthma in guinea pigs was diminished, meaning development of desensitization to the drug. This desensitization was prevented by pretreatment with mepacrine or indomethacin (ip, for 3 days). When the animals were pretreated with isoproterenol aerosol for 7 days, the direct relaxant effect of isoproterenol on isolated tracheal preparations was diminished significantly. After incubation with 1μM isoproterenol for 25 rain, the isolated guinea pig tracheal smooth muscle preparations became considerably less sensitive to the direct relaxant and spasmolytic effect of isoproterenol. The inhibitory effect of isoproterenol on anaphylactic contractions of ovalbumin-sensitized guinea pig tracheal preparations was also deminished. Preincubation with mepacrine, verapamil, dexamethasone and a-terpineol, an antiasthmatic principle of essential oil of Artemisia argyi, prevented the desensitization to the spasmolytic effect of isoproterenol. Arachidonic acid blocked the effect of mepacrine thin preventing desensitization The desensitizated preparations exhibited mainly decreased β-adrenergic receptor affinity to the agonists, and the development of desensitization seemed to be relevant to phospholipase A₂ activity and arachidonic acid.