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The role of adenosine in mast cell degranulation

Dexter, Emily Jane; (1999) The role of adenosine in mast cell degranulation. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

We have used a range of selective agonists and antagonists to examine the effect of adenosine in different mast cell phenotypes and on smooth muscle preparations. The agonists included the adenosine A1 receptor ligands R(-)N6-(2-phenylisopropyl)-adenosine (R-PIA) and N6-cyclopentyladenosine (CPA), the A2a and A2b compounds 2-p(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS21680) and N-[(2-methylphenyl)methyl]-adenosine (metrifudil), the A3 agents 1-deoxy-l-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-D-ribofuranuron-amide (IB-MECA) and N6-[2-(4-aminophenyl)ethyl]-adenosine (APNEA) and the non-selective agonist 5'-N-ethylcarboxamidoadenosine (NECA). The antagonists comprised the A1 ligand 8-cyclopentyl-l,3-dipropylxanthine (DPCPX), the A2 compound 9-chloro-2-(2-fliryl)[l,2,4]triazolo[l,5-c]quinazdin-5-amine (CGS15943), the A1/A2 ligand 8-phenyl-theophylline (8PT) and the A3 compound (E)-3-(3-(1,2,3,6-tetrahydro-2,6-dioxo-1,3-dipropyl-9H-purin-8-yl)phenyl) acrylic acid (BW3911). The agonists potentiated (by up to 120 %) immunologic histamine release from rat peritoneal mast cells with a rank order of potency of IB-MECA>metrifudil=CPA=NECA=R-PlA>CGS21680. The dose-response curve for IB-MECA was shifted to the right by BW3911, but was less affected by 8PT, DPCPX and CGS15943. Mechanistic studies showed augmented histamine release was coupled with a parallel rise in IP3 production, indicating the activation of A3 receptors. The agonists both induced histamine release (by up to 50 %) and potentiated secretagogue induced release from mouse peritoneal mast cells with the first effect probably the result of A3 receptor activation, and the second due to stimulation of either A2b or A3 receptors. In contrast, adenosine and its analogues inhibited (by up to 90 %) immunologic histamine release from human lung mast cells and basophils. In the basophil, IB-MECA was the most potent inhibitor, NECA showed significant activity and the remaining compounds were ineffective. In the lung, all of the agonists, apart from CGS21680, showed comparable activity. These data suggest that inhibition is mediated through A3 receptors in the basophil and A2b receptors in the lung mast cell. Adenosine was shown to have a dual effect on smooth muscle, inducing relaxation through A2 receptors and contraction thorough activating either A1 or A3 receptors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of adenosine in mast cell degranulation
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Adenosine
URI: https://discovery.ucl.ac.uk/id/eprint/10120092
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