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

Abstract

Background: Although the existence of functional β2-adrenoceptor on eosinophils has been reported, the effects of desensitization of β2-adrenoceptors on eosinophils have not been well documented. Objective: The effects of desensitization of β2-adrenoceptors on the degranulation of guinea pig eosinophils were investigated. Methods: Guinea pig eosinophils were 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 β2-agonists were abolished by pretreatment with KT5720, an inhibitor of protein kinase A. Desensitization of the inhibitory effects of β2-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 were 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 β2-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 were not affected by β2-adrenoceptor desensitization. Conclusions: Prolonged incubation with β2-agonists induced desensitization of β2-adrenoceptors. Also, we postulated that hypersensitization of phosphodiesterase to its inhibitors occurs in β2-adrenoceptor–desensitized guinea pig eosinophils. (J Allergy Clin Immunol 2000;106:896-903.)