ADENOSINE REDUCES AIRWAY EXCITATORY NONCHOLINERGIC (E-NC) CONTRACTIONTHROUGH BOTH A(1) AND A(2) ADENOSINE RECEPTOR ACTIVATION IN THE GUINEA-PIG

The influence of adenosine and selective A(1) and A(2) agonists and an tagonists was investigated on the cholinergic and the excitatory non-c holinergic (e-NC) contractions induced by electrical field stimulation in the guinea-pig bronchi. Adenosine (10 nM-1 mM) induced a concentra tion-dependent inhibition of the e-NC contraction (EC50 = 90 +/- 14 mu M), whereas the cholinergic peak was only slightly affected. Preincub ation of the tissue with the adenosine uptake blocker dipyridamole (10 mu M)) significantly shifted the concentration-inhibition curve to ad enosine to the left (EC50 = 10 +/- 1 mu M), suggesting an interaction with extracellular adenosine receptors of A(1) and/or A(2) subtype. To characterize the receptor type involved in this effect, selective ade nosine derivatives were studied. The agonist to both A(1) and A(2), ad enosine receptors, 5'-N-ethylcarboxamidoadenosine (NECA) was more pote nt than the selective A(1) agonist, (-)-R-6-phenylisopropyladenosine ( R-PIA), in inhibiting the e-NC contraction (EC50 = 0.10 +/- 0.04 and 0 .60 +/- 0.12 mu M, respectively, with a maximal inhibition of 70 and 4 5%, respectively). The concentration-response curve to NECA was shifte d to the right by the A(2) receptor selective antagonist 3,7-dimethyl- 1-propargylxanthine (DMPX) (10 mu M) (EC50 = 1.4 +/- 0.5 mu M) as well as by the specific A(1) receptor antagonist 8-cyclopentyl-1,3-dipropy lxanthine (DPCPX) (10 mu M) (EC50 = 0.7 +/- 0.3 mu M). The inhibitory effect induced by the association of both antagonists, DPCPX and DMPX, was considerably potentiated (EC50 > 22 +/- 25 mu M). The effect of R -PIA was also shifted to the right by DPCPX (EC50 = 8.2 +/- 1.6 mu M) but was not modified by DMPX. The contractile response to exogenous su bstance P was unaffected by NECA pretreatment (0.3 mu M). Altogether, these results suggest that adenosine-induced inhibition of e-NC contra ction of guinea-pig bronchi is mediated through activation of both A(1 ) and A(2) adenosine receptors linked to inhibition of the release of neuropeptides from C-fibre nerve endings.