Adenosine alone at 0.1 and 1.0 mg per tracheal segment stimulated mucus secretion by 52% and 88%, respectively, compared to baseline (P less than 0.0001). The site of the potent secretagogue effect of adenosine in canine trachea was consistent with A2 activation. A2 site activation and enhanced secretion were also induced by N-ethylcarboxamide adenosine and dipyridamole. N6-R-phenylisopropyl adenosine (PIA) and 2',5'-dideoxyadenosine (ddAdo) inhibited the adenosine-induced secretion (35% and 42%, respectively). However, when PIA or ddAdo were administered in conjunction with the potent phosphodiesterase inhibitor, methylisobutylxanthine (MIX), the effects of PIA were potentiated and the effects of ddAdo were reversed, yielding stimulation (A2) and antagonism (A1) of secretion, respectively. 8-Phenyltheophylline by aerosol was a very potent antagonist of the secretagogue effect of adenosine (70% inhibition; P less than 0.00001).