Modeling the response of the asthmatic airways to adenosine: Mechanisms and receptors

We describe a new experimental animal model which mimics closely the bronchoconstrictor effects of adenosine in asthmatics. Brown Norway (BN) rats were sensitized to ovalbumin (OA). Subsequent challenge with OA induced a marked and selective airway hyperresponsiveness to adenosine. The augmented response to adenosine was blocked selectively by disodium cromoglycate, methysergide, and theophylline and associated with increases in the plasma concentrations of histamine and 5-HT and degranulation of airway mast cells. The broad-spectrum adenosine receptor agonist, NECA, also induced bronchoconstriction in actively sensitized (AS), OA-challenged animals, whereas agonists selective for A 1 , A 2A , and A3 receptors induced minimal effects. MRS 1754, which has similar affinity for rat A 2B and A 1 receptors, failed to block the response to adenosine, despite blocking the A 1 receptor-mediated bradycardia-induced by NECA. 8-SPT and CGS 15943, antagonists at A 1 , A 2A , and A 2B but not As receptors, inhibited the bronchoconstrictor response to adenosine by 3-fold but only at doses yielding plasma concentrations 139 and 21 times greater than their respective KB values at the rat A 2B receptor. Adenosine and NECA, but not CPA, CGS 21680, or 2-CI-IB-MECA, induced contraction of parenchymal strip preparations from AS, 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 A 2B receptor. Upregulation by allergic activation, mast cell dependency, and selective blockade by theophylline represent striking similarities between the bronchoconstrictor response to adenosine in the BN rat and that on the airways of asthmatics. However, the receptor mediating the response in the rat cannot be categorized as one of the four recognized adenosine receptor subtypes.