The receptor mechanism mediating the contractile response to adenosine on lung parenchymal strips from actively sensitised,allergen-challenged Brown Norway rats

Parenchymal strips prepared from lungs removed from actively sensitised Brown Norway rats challenged with allergen show hyperresponsiveness to adenosine. The response is mast cell mediated and a preliminary pharmacological analysis suggested the involvement of a receptor (or receptors) that could not be classified as any of the known adenosine receptor subtypes. We present a further analysis of the response. Male Brown Norway (BN) rats, actively sensitised to ovalbumin (OA), were challenged intratracheally with OA and killed 3 h later to provide parenchymal strip preparations. The augmented contractile responses to adenosine were partially blocked by the 5-HT receptor antagonist, methysergide, or the A₁ receptor antagonist, DPCPX, and abolished in the presence of both antagonists. Responses to high concentrations of the A₁ receptor agonist, CPA were, like those to adenosine, augmented on tissues from allergen-challenged animals and blocked by a combination of methysergide and DPCPX. The A₃ receptor agonist, Cl-IB-MECA, did not contract the tissue, but partially blocked the response to adenosine. A combination of Cl-IB-MECA and methysergide induced a similar degree of blockade to that seen with either drug given alone. Combination of Cl-IB-MECA and/or methysergide with DPCPX abolished the response to adenosine. The effects of the A₃ receptor agonist, inosine, were augmented on tissues from allergen-challenged animals and markedly inhibited by disodium cromoglycate, methysergide or Cl-IB-MECA. Responses to adenosine were abolished when parenchymal strips were taken from rats pretreated 48 h previously with pertussis toxin. 8-SPT, CGS 15943, XAC, MRS 1754, DPCPX and theophylline, at concentrations which inhibit the A₁ A_2A and/or A_2B receptors but have negligible affinity for the rat A₃ receptor, inhibited responses to adenosine, but high concentrations were required and blockade was incomplete. MRS 1523 and MRS 1191, which are antagonists at the rat A₃ receptor, had no effect on the response to adenosine. The present results support and clarify our earlier conclusion that an atypical receptor mechanism mediates contraction of the parenchymal strip prepared from the lungs of actively sensitised BN rats challenged with allergen to adenosine. The response arises from a combined effect of adenosine on the A₁ receptor and a receptor with similarities to the A₃ receptor, but where Cl-IB-MECA behaves as an antagonist and MRS 1523 and MRS 1191 are inactive at concentrations that substantially exceed their affinities for the rat A₃ receptor.A part of this work was presented to the British Pharmacological Society in January 2003