Pharmacological characterisation of the adenosine receptor mediating increased ion transport in the mouse isolated trachea and the effect of allergen challenge

Abstract

The effect of adenosine on transepithelial ion transport was investigated in isolated preparations of murine trachea mounted in Ussing chambers. The possible regulation of adenosine receptors in an established model of allergic airway inflammation was also investigated. Mucosally applied adenosine caused increases in short-circuit current (I SC) that corresponded to approximately 50% of the response to the most efficacious secretogogue, ATP (ΔI SC 69.5 ± 6.7 μA cm 2). In contrast, submucosally applied adenosine caused only small (< 20%) increases in I SC, which were not investigated further. The A 1-selective (N 6-cyclopentyladenosine, CPA, 1 nM-10 μM), A 2A- selective (2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxoamido adenosine; CGS 21680; 0.1-100 μM) and A 3-selective (1-deoxy-1-[6-[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-N-methyl-β-D- ribofuranuronamide; IB-MECA; 30 nM-100 μM) adenosine receptor agonists were either equipotent or less potent than adenosine, suggesting that these receptors do not mediate the response to adenosine. The A 1 receptor selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 10 nM-1 μM) caused a rightward shift of the adenosine concentration-effect curve only at 1 μM. The mixed A 2A/A 2B receptor antagonist 4-(2-[7-amino-2-(2- furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) also caused rightward shift of the adenosine concentration-effect curve, again only at micromolar concentrations, suggestive of the involvement of A 2B receptors. In preparations from animals sensitised to ovalbumin and challenged over 3 days with aerosol ovalbumin, a decrease in baseline I SC was observed and responses to ATP were diminished. Similarly, the amplitude of responses to adenosine were attenuated although there was no change in potency. These results suggest that the A 2B receptor mediates the I SC response to adenosine in the mouse trachea. This receptor does not appear to be regulated in a standard asthma model. © 2005 Nature Publishing Group. All rights reserved.