Evidence for an atypical receptor mediating the augmented bronchoconstrictor response to adenosine induced by allergen challenge in actively sensitized Brown Norway rats

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Abstract
The bronchoconstrictor response to adenosine is markedly and selectively increased following ovalbumin (OA) challenge in actively sensitized, Brown Norway rats. We present a pharmacological analysis of the receptor mediating this response. Like adenosine, the broad‐spectrum adenosine receptor agonist, NECA, induced dose‐related bronchoconstriction in actively sensitized, OA‐challenged animals. In contrast, CPA, CGS 21680 and 2‐Cl‐IB‐MECA, agonists selective for A1 A2A and A3 receptors, respectively, induced no, or minimal, bronchoconstriction. Neither the selective A1 receptor antagonist, DPCPX, nor the selective A2A receptor antagonist, ZM 241385, blocked the bronchoconstrictor response to adenosine. MRS 1754, which has similar affinity for rat A2B and A1 receptors, failed to block the bronchoconstrictor response to adenosine despite blockade of the A1 receptor‐mediated bradycardia induced by NECA. 8‐SPT and CGS 15943, antagonists at A1, A2A, and A2B but not A3 receptors, inhibited the bronchoconstrictor response to adenosine. However, the degree of blockade (approximately 3 fold) did not reflect the plasma concentrations, which were 139 and 21 times greater than the KB value at the rat A2B receptor, respectively. Adenosine and NECA, but not CPA, CGS 21680 or 2‐Cl‐IB‐MECA, induced contraction of parenchymal strip preparations from actively sensitized OA‐challenged animals. Responses to adenosine could not be antagonized by 8‐SPT or MRS 1754 at concentrations >50 times their affinities at the rat A2B receptor. The receptor mediating the bronchoconstrictor response to adenosine augmented following allergen challenge in actively sensitized BN rats cannot be categorized as one of the four recognized adenosine receptor subtypes. British Journal of Pharmacology (2002) 135, 685–696; doi:10.1038/sj.bjp.0704516