SMOOTH-MUSCLE RELAXANT ACTIVITY OF A1-SELECTIVE AND A2-SELECTIVE ADENOSINE RECEPTOR AGONISTS IN GUINEA-PIG TRACHEA - INVOLVEMENT OF POTASSIUM CHANNELS

The relaxant activities of N-6-cyclopentyladenosine (CPA), an Al-selec tive agonist, and of 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), a potent A2-receptor agonist, in the carbachol-contracted guinea pig is olated trachea have been evaluated. Both CPA and CPCA induced concentr ation-dependent relaxations of the guinea pig trachea, CPCA demonstrat ing a more potent but less efficient activity. 8-Cyclopentyl-1,3-dimet hylxanthine (CPT) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (10 m u M), both selective and potent Al-adenosine receptor antagonists, ind uced only a weak inhibition of CPA while 3,7-dimethyl-1-propargylxanth ine (DMPX) (10 mu M), a selective A2-adenosine receptor antagonist, fa iled to antagonize the relaxant activity of CPA. These results indicat e that a major component of the tracheal relaxant activity of CPA occu rred by a mechanism which is insensitive to the antagonist potency of Al- and Al-xanthine adenosine antagonists and therefore was not mediat ed by Al- or Al-adenosine receptors activation. The relaxant activity of CPCA was inhibited by DMPX, which supported the involvement of A2-a denosine receptors. Glibenclamide (10 mu M), an inhibitor of K-ATP-cha nnels, inhibited the relaxant activity of CPCA, whereas it was without effect on CPA. Iberiotoxin (180 nM), an inhibitor of the large-conduc tance CA(2+)-activated K+-channel, inhibited the relaxant action of CP A and CPCA. However, verapamil can offset the inhibition of CPA provid ed by iberiotoxin which suggests that such an antagonism does not repr esent an interaction between the toxin and CPA at the level of the lar ge-conductance CA2(+)-activated K+-channel gating but rather functiona l antagonism attributable to the promotion of CA2(+) influx by the tox in. In contrast, verapamil only partially reversed the inhibition of C PCA relaxant activity provided by iberiotoxin. Taken together, these r esults suggest that A2-adenosine receptor subtypes are coupled to KATP -channels and large-conductance CA2(+)-activated K+-channels in the gu inea pig trachea whereas the unidentified adenosine receptor subtype, involved in CPA relaxant activity, is not.