Desensitization of beta2-adrenoceptor and hypersensitization to phosphodiesterase inhibitors elicited by beta2-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 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.
Mio
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Kirino
Y
Y
Kamei
C
C
D000318:Adrenergic beta-Agonists / Q000378:metabolism* / Q000494:pharmacology; D000420:Albuterol / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000378:metabolism / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002227:Carbazoles; D002478:Cells, Cultured; D002976:Clenbuterol / Q000378:metabolism / Q000494:pharmacology; D005576:Colforsin / Q000378:metabolism / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047209:Eosinophil Peroxidase; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005280:Fenoterol / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D010544:Peroxidases; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013806:Theophylline / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007476:Ionophores; D010726:Phosphodiesterase Inhibitors; D011758:Pyrroles; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D005280:Fenoterol; D000001:Calcimycin; C057416:KT 5720; D003994:Bucladesine; D013806:Theophylline; D000242:Cyclic AMP; D047209:Eosinophil Peroxidase; D010544:Peroxidases; D017868:Cyclic AMP-Dependent Protein Kinases; D000420:Albuterol; D002976:Clenbuterol