Adenosine A3 receptors on human eosinophils mediate inhibition of degranulation and superoxide anion release

1 The role of adenosine A, receptors on human eosinophil degranulation and superoxide anion (O-2(-)) release was studied in vitro using the complement fragment C5a as the main stimulus and employing a number of selective agonists and antagonists. 2 In the presence of cytochalasin B (CB), C5a induced a dose-dependent release of the granular eosinophil pel oxidase (EPO), but not O-2, whereas in the absence of CB O-2, but not EPO, was released. 3 C5a-induced EPO release was inhibited dose-dependently by the selective A(3) agonist N-6-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) and to a lesser extent by the less-selective N-6-2-(4-amino-3-iodophenyl) ethyladenosine (APNEA). The IC50 (95% CI) for IB-MECA was 6.8 mu m (3.1-12.0 mu m). At concentrations up to 100 mu M, neither adenosine nor the selective A(1) agonist N-cyclopentyladenosine (CPA) and the selective A(2) agonist 2-[[2-[4-(2-carboxyethyl)phenyl]ethyl]amino]-N-ethylcarboxamidoadenosine (CGS 21680) had any significant effect. 4 The inhibitory effect of IB-MECA was almost completely abolished by pre-treatment with 1 mu M of the selective A, antagonist 9-chloro-2-(2-furyl)-5-phenylactylamino[1,2,4]triazolo[1,5-c]quinazoline (MRS 1220), but not the selective Al antagonist 1,3-diplopyly-8-cyclopentylxanthine (DPCPX) or the selective A, antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). 5 IB-MECA also significantly inhibited C5a-induced O-2(-) release with IC50 (95% CI) of 9.5 mu M (4.6-13.1 mu M) whereas adenosine and the Al agonist CPA potentiated this effect at low concentrations. The potentiation appeared to be a result of their direct O-2(-) release from these cells, probably mediated via A(1) receptors. The inhibition by IB-MECA was selectively reversed by MRS 1220. 6 These results show that the A(3) receptors on human eosinophils mediate inhibition of both degranulation and O-2(-) release and suggest a therapeutic potential for A(3) agonists in diseases such as asthma in which activated eosinophils are involved.