Desensitization of β2-adrenoceptor and hypersensitization to phosphodiesterase inhibitors elicited by β2-agonists in guinea pig eosinophils

Background: Although the existence of functional beta (2)-adrenoceptor on eosinophils has been reported, the effects of desensitization of beta (2)-adrenoceptors on eosinophils have not been well documented. Objective: The effects of desensitization of beta (2)-adrenoceptors on the degranulation of guinea pig eosinophils were investigated. Methods: Guinea pig eosinophils mere stimulated with the calcium ionophore A23187, and eosinophil peroxidase (EPO) release was determined. Changes in intracellular cyclic adenosine monophosphate (cAMP) levels were also measured. Results: A23187-induced EPO release from guinea pig eosinophils was inhibited in a concentration-dependent manner by pretreatment for 5 minutes with fenoterol, clenbuterol, and salbutamol, Such effects of beta (2)-agonists were abolished by pretreatment with KT5720, an inhibitor of protein kinase A. Desensitization of the inhibitory effects of beta (2)-agonists was observed when the incubation time was prolonged. Fenoterol (10(-6) mol/L) induced almost complete desensitization after 120 minutes of incubation, whereas clenbuterol did not bring about significant desensitization. The inhibitory effects of fenoterol and clenbuterol on A23187-induced EPO release mere correlated with increases in the intracellular cAMP levels evoked by either compound. After incubation of eosinophils with 10(-6) mol/L fenoterol for 120 minutes to induce complete desensitization of beta (2)-adrenoceptors, the inhibitory effects of theophylline and rolipram were increased by about 100-fold in the desensitized cells, although the effects of forskolin and dibutyryl cAMP mere not affected by beta (2)-adrenoceptor desensitization. Conclusions: Prolonged incubation with beta (2)-agonists induced desensitization of beta (2)-adrenoceptors. Also, we postulated that hypersensitization of phosphodiesterase to its inhibitors occurs in beta (2)-adrenoceptor-desensitized guinea pig eosinophils.