Differential Effects of β_2-Adrenoceptor Desensitization on the IgE-Dependent Release of Chemical Mediators from Cultured Human Mast Cells(Pharmacology)

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In the present study, we examined the inhibitory effects of the β_2-adrenoceptor agonists isoproterenol, salbutamol, fenoterol, and clenbuterol, on the release of chemical mediators from cultured human mast cells after prolonged treatment with the agonists. Although preincubation of sensitized mast cells for 10 min with β_2-adrenoceptor agonists potently inhibited mediator release, prolongation of the preincubation period up to 240 min attenuated the inhibition. The attenuation of histamine release inhibition was potent when compared with that of prostaglandin D_2 (PGD_2) and cysteinyl leukotriene (LT) release inhibition. In contrast, forskolin inhibited mediator release and the inhibition increased gradually in proportion to the preincubation period. The reduced inhibition by the β_2-adrenoceptor agonists was compensated for by simultaneous treatment with cholera toxin. The β_2-adrenoceptor agonists elevated intracellular cAMP levels after 10-min incubation and the elevated levels were almost comparable to those after 240-min incubation. Forskolin elevated the intracellular cAMP levels more potently after incubation for 240min than after 10min. When mast cells were incubated for 3d with the β_2-adrenoceptor agonists, similar attenuation of mediator release inhibition was observed. Elevation of intracellular cAMP levels was also attenuated, although β_2-adrenoceptor mRNA expression was potentiated. The present results collectively indicate that the attenuation of mediator release inhibition by β_2-adrenoceptor agonists under the present experimental conditions involves uncoupling between β_2-adrenoceptors and Gs proteins. Furthermore, the β_2-adrenoceptor desensitization causes differential attenuating effects on the inhibition of histamine, PGD_2, and LT release, suggesting that downstream events involved in each inhibitory pathway have different sensitivity to receptor desensitization.
社団法人日本薬学会の論文
2004-10-01

Differential Effects of β_2-Adrenoceptor Desensitization on the IgE-Dependent Release of Chemical Mediators from Cultured Human Mast Cells(Pharmacology)

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