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Wednesday 01 November 2000

Desensitization of beta2-adrenoceptor and hypersensitization to phosphodiesterase inhibitors elicited by beta2-agonists in guinea pig eosinophils.

By: Mio M, Kirino Y, Kamei C.

J Allergy Clin Immunol 2000 Nov;106(5):896-903

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 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 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 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 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 were 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.

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