Smooth muscle relaxant activity of A1- and A2-selective adenosine receptor agonists in guinea pig trachea: involvement of potassium channels.

The relaxant activities of N6-cyclopentyladenosine (CPA), an A1-selective agonist, and of 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), a potent A2-receptor agonist, in the carbachol-contracted guinea pig isolated trachea have been evaluated. Both CPA and CPCA induced concentration-dependent relaxations of the guinea pig trachea, CPCA demonstrating a more potent but less efficient activity. 8-Cyclopentyl-1,3-dimethylxanthine (CPT) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (10 microM), both selective and potent A1-adenosine receptor antagonists, induced only a weak inhibition of CPA while 3,7-dimethyl-1-propargylxanthine (DMPX) (10 microM), a selective A2-adenosine receptor antagonist, failed to antagonize the relaxant activity of CPA. These results indicate that a major component of the tracheal relaxant activity of CPA occurred by a mechanism which is insensitive to the antagonist potency of A1- and A1-xanthine adenosine antagonists and therefore was not mediated by A1- or A1-adenosine receptors activation. The relaxant activity of CPCA was inhibited by DMPX, which supported the involvement of A2-adenosine receptors. Glibenclamide (10 microM), an inhibitor of KATP-channels, inhibited the relaxant activity of CPCA, whereas it was without effect on CPA. Iberiotoxin (180 nM), an inhibitor of the large-conductance CA2(+)-activated K+ channel, inhibited the relaxant action of CPA and CPCA. However, verapamil can offset the inhibition of CPA provided by iberiotoxin which suggests that such an antagonism does not represent an interaction between the toxin and CPA at the level of the large-conductance CA2(+)-activated K(+)-channel gating but rather functional antagonism attributable to the promotion of CA2+ influx by the toxin. In contrast, verapamil only partially reversed the inhibition of CPCA relaxant activity provided by iberiotoxin. Taken together, these results suggest that A2-adenosine receptor subtypes are coupled to KATP-channels and large-conductance CA2(+)-activated K(+)-channels in the guinea pig trachea whereas the unidentified adenosine receptor subtype, involved in CPA relaxant activity, is not.