Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 27, Issue 10, Pages 1549-1554Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.27.1549
Keywords
beta(2)-adrenoceptor agonist; desensitization; human cultured mast cell; IgE; chemical mediator
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In the present study, we examined the inhibitory effects of the beta(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 beta(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 beta(2)-adrenoceptor agonists was compensated for by simultaneous treatment with cholera toxin. The beta(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 240 min than after 10 min. When mast cells were incubated for 3d with the beta(2)-adrenoceptor agonists, similar attenuation of mediator release inhibition was observed. Elevation of intracellular cAMP levels was also attenuated, although beta(2)-adrenoceptor mRNA expression was potentiated. The present results collectively indicate that the attenuation of mediator release inhibition by beta(2)-adrenoceptor agonists under the present experimental conditions involves uncoupling between beta(2)-adrenoceptors and Gs proteins. Furthermore, the beta(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.
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