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Further pharmacological characterization of the adenosine receptor subtype mediating inhibition of oxidative burst in human isolated neutrophils

Further pharmacological characterization of the adenosine receptor subtype mediating inhibition... The aims of this study were to characterize the adenosine receptor subtype mediating inhibition of superoxide anion generation induced by N‐formyl‐methionyl‐leucylphenylalanine (fMLP) in human neutrophils and to test the hypothesis that adenosine 3′:5′‐cyclic monophosphate (cAMP) is the second messenger mediating such inhibition. Superoxide anion generation induced by a submaximal concentration of fMLP (1 μM) was inhibited in a concentration‐dependent manner by adenosine receptor agonists with a rank order of potency ofN‐ethylcarboxamidoadenosine (NECA) > 2(4‐((2‐ carboxyethyl)phenyl)ethylamino)‐5′‐N‐ethylcarboxamido adenosine (CGS 21680) > (R)‐N6‐phenyl‐2‐propyladenosine ((R)‐PIA) > 2‐Chloro‐N6‐(3‐iodobenzyl)9‐(5‐methylcarbamoyl)‐β‐D‐ribofuranosyl) adenine (2‐Cl‐IB‐MECA) > N6‐cyclopentyladenosine (CPA) > (S)‐N6‐phenyl‐2‐propyladenosine ((S)‐PIA) ≥ N6‐(4‐amino‐3‐iodobenzyl) adenosine‐5′‐N‐methyl‐uronamide (AB‐MECA); this order of potency is consistent with the activation of A2A adenosine receptors. The nonselective A1, A2A, and A2B receptor antagonist 8‐p‐(sulphophenyl) theophylline (8‐SPT; 10 μM) produced blockade of each of the agonists (pKB values 4.79–5.68). The selective A1 adenosine receptor antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX; 100 nM) and the selective A3 adenosine receptor antagonist 3‐(3‐iodo‐4‐aminobenzyl)‐8‐(4‐oxyacetate)phenyl‐1‐propylxanthine (I‐ABOPX; 200 nM) also produced blockade of all the agonists (PKB values 7.37–7.61 and 6.75–7.52, respectively); however, the concentrations required were higher than those which are considered selective for the A1 or A3 receptors. The selective A2A receptor antagonist, 4‐(2‐(7‐amino‐2‐(2‐furyl) (1,2,4) triazolo (2,3‐a) (1,3,5) triazin‐5‐yl amino)ethyl) phenol (ZM 241385; 100 nM), powerfully suppressed the inhibition of the oxidative burst induced by each of the agonists. A Schild analysis of the effects of ZM 241385, 1–100 nM, against NECA and CGS 21680 was carried out. ZM 241385 produced concentration‐dependent, parallel shifts of the concentration–effect curves to both NECA and CGS 21680, with pA2 values of 9.62 and 9.59, respectively. Together, these data establish that inhibition of the oxidative burst in human isolated neutrophils, induced by adenosine receptor agonists, is mediated by the A2A receptor. NECA (0.01–10 μM) induced a concentration‐dependent increase in the intracellular cAMP content of neutrophils. This effect was inhibited in a dose‐dependent manner by ZM 241385 (0.001–10 μM), consistent with activation of A2A adenosine receptors. The results clearly demonstrate that in human neutrophils inhibition of the fMLP—induced oxidative burst by adenosine receptor agonists is mediated via activation of A2A adenosine receptors linked positively to cAMP. No evidence of A1, A2B, or A3 adenosine receptor‐mediated modulation of oxidative burst was found. Drug Dev. Res. 43:214–224, 1998. © 1998 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drug Development Research Wiley

Further pharmacological characterization of the adenosine receptor subtype mediating inhibition of oxidative burst in human isolated neutrophils

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Publisher
Wiley
Copyright
Copyright © 1998 Wiley‐Liss, Inc.
ISSN
0272-4391
eISSN
1098-2299
DOI
10.1002/(SICI)1098-2299(199804)43:4<214::AID-DDR5>3.3.CO;2-4
Publisher site
See Article on Publisher Site

Abstract

The aims of this study were to characterize the adenosine receptor subtype mediating inhibition of superoxide anion generation induced by N‐formyl‐methionyl‐leucylphenylalanine (fMLP) in human neutrophils and to test the hypothesis that adenosine 3′:5′‐cyclic monophosphate (cAMP) is the second messenger mediating such inhibition. Superoxide anion generation induced by a submaximal concentration of fMLP (1 μM) was inhibited in a concentration‐dependent manner by adenosine receptor agonists with a rank order of potency ofN‐ethylcarboxamidoadenosine (NECA) > 2(4‐((2‐ carboxyethyl)phenyl)ethylamino)‐5′‐N‐ethylcarboxamido adenosine (CGS 21680) > (R)‐N6‐phenyl‐2‐propyladenosine ((R)‐PIA) > 2‐Chloro‐N6‐(3‐iodobenzyl)9‐(5‐methylcarbamoyl)‐β‐D‐ribofuranosyl) adenine (2‐Cl‐IB‐MECA) > N6‐cyclopentyladenosine (CPA) > (S)‐N6‐phenyl‐2‐propyladenosine ((S)‐PIA) ≥ N6‐(4‐amino‐3‐iodobenzyl) adenosine‐5′‐N‐methyl‐uronamide (AB‐MECA); this order of potency is consistent with the activation of A2A adenosine receptors. The nonselective A1, A2A, and A2B receptor antagonist 8‐p‐(sulphophenyl) theophylline (8‐SPT; 10 μM) produced blockade of each of the agonists (pKB values 4.79–5.68). The selective A1 adenosine receptor antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX; 100 nM) and the selective A3 adenosine receptor antagonist 3‐(3‐iodo‐4‐aminobenzyl)‐8‐(4‐oxyacetate)phenyl‐1‐propylxanthine (I‐ABOPX; 200 nM) also produced blockade of all the agonists (PKB values 7.37–7.61 and 6.75–7.52, respectively); however, the concentrations required were higher than those which are considered selective for the A1 or A3 receptors. The selective A2A receptor antagonist, 4‐(2‐(7‐amino‐2‐(2‐furyl) (1,2,4) triazolo (2,3‐a) (1,3,5) triazin‐5‐yl amino)ethyl) phenol (ZM 241385; 100 nM), powerfully suppressed the inhibition of the oxidative burst induced by each of the agonists. A Schild analysis of the effects of ZM 241385, 1–100 nM, against NECA and CGS 21680 was carried out. ZM 241385 produced concentration‐dependent, parallel shifts of the concentration–effect curves to both NECA and CGS 21680, with pA2 values of 9.62 and 9.59, respectively. Together, these data establish that inhibition of the oxidative burst in human isolated neutrophils, induced by adenosine receptor agonists, is mediated by the A2A receptor. NECA (0.01–10 μM) induced a concentration‐dependent increase in the intracellular cAMP content of neutrophils. This effect was inhibited in a dose‐dependent manner by ZM 241385 (0.001–10 μM), consistent with activation of A2A adenosine receptors. The results clearly demonstrate that in human neutrophils inhibition of the fMLP—induced oxidative burst by adenosine receptor agonists is mediated via activation of A2A adenosine receptors linked positively to cAMP. No evidence of A1, A2B, or A3 adenosine receptor‐mediated modulation of oxidative burst was found. Drug Dev. Res. 43:214–224, 1998. © 1998 Wiley‐Liss, Inc.

Journal

Drug Development Research – Wiley

Published: Apr 1, 1998

Keywords: A 1 , A 2 , A 3 adenosine receptors; human neutrophils; fMLP‐induced oxidative burst; adenosine receptor agonists; adenosine receptor antagonists

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