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

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. Keywords: Adenosine receptors, airway hyperresponsiveness, allergen challenge, Brown Norway rat, lung parenchymal strip Introduction We have recently described a marked and selective augmentation of the bronchoconstrictor response to adenosine following allergen challenge in actively sensitized, Brown Norway (BN) rats (Fozard & Hannon, 2000; Hannon et al., 2001). The response occurs against a background of mild pulmonary inflammation (Palser et al., 2000), exhibits tachyphylaxis (Fozard & Hannon, 2000) and is primarily, if not exclusively, a consequence of mast cell activation (Hannon et al., 2001). In all these respects it bears similarity to the bronchoconstrictor response to inhaled adenosine seen in asthmatic patients (Phillips & Holgate, 1995; Jacobson & Bai, 1997; Marquardt, 1997; Polosa & Holgate, 1997; Feoktistov et al., 1998; Forsythe & Ennis, 1999; Meade et al., 2001). The receptor mediating the bronchoconstrictor response to adenosine in asthmatics has not been established, although evidence is available implicating the A2B receptor (Feoktistov et al., 1998; Fozard & Hannon, 1999). The aim of the present work was to characterize the receptor(s) mediating the bronchoconstrictor response to adenosine, augmented following allergen challenge, in actively sensitized BN rats. To this end, the effect of allergen challenge on the sensitivity of the airways to a range of subtype selective adenosine receptor agonists was defined both in vivo and in vitro. In addition, the effects of a series of adenosine receptor antagonists, some of them subtype selective, on the augmented bronchoconstrictor response to adenosine were investigated. A part of these results has been presented to the British Pharmacological Society (Hannon et al., 1999a, 1999b; Fozard et al., 2001).