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Activation of phosphoinositide breakdown and elevation of intracellular calcium in a rat RBL‐2H3 mast cell line by adenosine analogs: Involvement of A 3 ‐adenosine receptors?
Author(s) -
Shin Yangmee,
Daly John W.,
Jacobson Kenneth A.
Publication year - 1996
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(19960901)39:1<36::aid-ddr5>3.0.co;2-l
Subject(s) - adenosine , adenosine receptor , agonist , receptor , chemistry , intracellular , endocrinology , medicine , pharmacology , biology , biochemistry
A variety of adenosine analogs activate phosphoinositide breakdown in a rat RBL‐2H3 mast cell line. It is presumed that an A 3 ‐adenosine receptor is involved, since the phosphoinositide response is insensitive to xanthines. However, the very potent A 3 ‐ receptor agonist 2‐chloro‐N 6 ‐iodobenzyl‐N‐methylcarboxamidoadenosine (2‐Cl‐IBMECA) with an EC 50 of 4.1 μM is about twofold less potent (and less efficacious) than N‐ethylcarboxamidoadenosine (NECA) with an EC 50 of 2.1 μM. The other agents consisting of N 6 ‐ p ‐aminophenylethyladenosine (APNEA), N 6 ‐iodobenzylMECA (IB‐MECA), N 6 ‐R‐ phenylisopropyladenosine (R‐PIA), 2‐chloroadenosine, N 6 ‐benzyladenosine, N 6 ‐ cyclohexyladenosine (CHA), N 6 ‐cyclohexylNECA (CHNECA), 2‐( p ‐ carboxyethylphenyl‐ethylaminoNECA (CGS 21680), 1,3‐dibutylxanthine 7‐riboside‐5′‐N‐methylcarboxamide (DBXRM), adenosine, and 8‐bromoadenosine are all nearly equipotent with EC 50 values of 5.5–13.9 μM. The rank order of potencies of the analogs in causing an elevation of intracellular calcium is quite different. The potent A 3 receptor agonists 2‐Cl‐IBMECA and IB‐MECA with EC 50 values of 0.07 and 0.11 μM, respectively, are about fourfold more potent than N 6 ‐cyclohexylNECA and about 15‐fold more potent than NECA. The other analogs are comparable or somewhat less potent than NECA, some are less efficacious, and 8‐bromoadenosine is inactive. The results suggest that stimulation of phosphoinositide breakdown by adenosine analogs in RBL‐2H3 cells as measured by IP 1 accumulation is not predictive of IP 3 ‐mediated elevations of intracellular calcium. Rank order of potency for the calcium response is consonant with intermediacy of A 3 ‐adenosine receptors, while the former, as measured by [ 3 H]IP 1 ‐formation, probably reflects contributions from both an A 3 ‐mediated response and some other mechanism. Combinations of subthreshold concentrations of 2‐Cl‐IBMECA with either the A 1 ‐selective agonist CHA or the A 2A ‐selective agonist CGS 21680 caused a marked stimulation of phosphoinositide breakdown, providing further evidence for dual mechanisms. The selective A 3 ‐adenosine receptor antagonist 3,6‐dichloro‐2′‐(isopropyloxy)‐4′‐methylflavone (MRS 1067) inhibits 2‐Cl‐IBMECA‐ and NECA‐elicited elevation of calcium levels, and had differential effects on phosphoinositide breakdown, blocking [ 3 H]IP 3 accumulation and either blocking (NECA) or having no effect (2‐Cl‐IBMECA) on [ 3 H]IP 1 accumulation. Drug Rev. Res. 39:36–46. © 1997 Wiley‐Liss, Inc.