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

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Abstract
The role of adenosine A3 receptors on human eosinophil degranulation and superoxide anion (O2−) release was studied in vitro using the complement fragment C5a as the main stimulus and employing a number of selective agonists and antagonists. In the presence of cytochalasin B (CB), C5a induced a dose‐dependent release of the granular eosinophil peroxidase (EPO), but not O2−, whereas in the absence of CB O2−, but not EPO, was released. C5a‐induced EPO release was inhibited dose‐dependently by the selective A3 agonist N6‐(3‐iodobenzyl)‐5′‐N‐methylcarbamoyladenosine (IB‐MECA) and to a lesser extent by the less‐selective N6‐2‐(4‐amino‐3‐iodophenyl) ethyladenosine (APNEA). The IC50 (95% CI) for IB‐MECA was 6.8 μM (3.1–12.0 μM). At concentrations up to 100 μM, neither adenosine nor the selective A1 agonist N‐cyclopentyladenosine (CPA) and the selective A2 agonist 2‐[[2‐[4‐(2‐carboxyethyl)phenyl]ethyl]amino]‐N‐ethylcarboxamidoadenosine (CGS 21680) had any significant effect. The inhibitory effect of IB‐MECA was almost completely abolished by pre‐treatment with 1 μM of the selective A3 antagonist 9‐chloro‐2‐(2‐furyl)‐5‐phenylactylamino[1,2,4]triazolo[1,5‐c]quinazoline (MRS 1220), but not the selective A1 antagonist 1,3‐dipropyly‐8‐cyclopentylxanthine (DPCPX) or the selective A2 antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX). IB‐MECA also significantly inhibited C5a‐induced O2− release with IC50 (95% CI) of 9.5 μM (4.6–13.1 μM) whereas adenosine and the A1 agonist CPA potentiated this effect at low concentrations. The potentiation appeared to be a result of their direct O2− release from these cells, probably mediated via A1 receptors. The inhibition by IB‐MECA was selectively reversed by MRS 1220. These results show that the A3 receptors on human eosinophils mediate inhibition of both degranulation and O2− release and suggest a therapeutic potential for A3 agonists in diseases such as asthma in which activated eosinophils are involved. British Journal of Pharmacology (1999) 127, 188–194; doi:10.1038/sj.bjp.0702476

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