Further pharmacological characterization of the adenosine receptor subtype mediating inhibition of oxidative burst in human isolated neutrophils
✍ Scribed by J.P. Hannon; K.M. Bray-French; R.M. Phillips; J.R. Fozard
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 282 KB
- Volume
- 43
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
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 of N-ethylcarboxamidoadenosine
this order of potency is consistent with the activation of A 2A adenosine receptors. The nonselective A 1 , A 2A , and A 2B receptor antagonist 8-p-(sulphophenyl) theophylline (8-SPT; 10 µM) produced blockade of each of the agonists (pK B values 4.79-5.68). The selective A 1 adenosine receptor antagonist 1,3dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM) and the selective A 3 adenosine receptor antagonist 3-(3iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine (I-ABOPX; 200 nM) also produced blockade of all the agonists (PK B 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 A 1 or A 3 receptors. The selective A 2A 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 pA 2 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 A 2A 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 A 2A 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 A 2A adenosine receptors linked positively to cAMP. No evidence of A 1 , A 2B , or A 3 adenosine receptor-mediated modulation of oxidative burst was found.