Adenosine receptor‐mediated contraction and relaxation of guinea‐pig isolated tracheal smooth muscle: effects of adenosine antagonists

The effects of several adenosine analogues and antagonists on guinea‐pig isolated trachea have been examined. 5′‐N‐ethylcarboxamidoadenosine (NECA), 5′‐N‐methylcarboxamidoadenosine (MECA) and adenosine (in the presence and absence of dipyridamole) elicited concentration‐dependent tracheal relaxation. The R(−)− and S(+)‐enantiomers of N⁶‐(2‐phenylisopropyl)adenosine (R‐PIA and S‐PIA respectively), N⁶‐cyclohexyladenosine (CHA) and 2‐chloroadenosine (CADO) caused contractions at low concentrations (0.05–2.0 μm), whereas at higher concentrations, relaxation resulted. For tracheal relaxation, the adenosine analogues exhibited the following rank order of potency: NECA > CADO > R‐PIA = MECA > S‐PIA > adenosine. The rank order of potency for inducing contractions was R‐PIA > CHA > CADO > S‐PIA. These data suggest that relaxation is mediated by adenosine A₂‐receptors, whereas contraction is the result of activation of A₁‐receptors. 8‐Phenyltheophylline (8‐PT), aminophylline, the triazoloquinazoline CGS 15943A and NPC205 (1,3‐di‐n‐propyl‐8‐(4‐hydroxyphenyl)xanthine) each inhibited the R‐PIA‐induced contractile response, whereas enprofylline was without effect. NPC205, aminophylline and 8‐PT were competitive antagonists, but CGS15943A was non‐competitive. That the most potent antagonist was the A₁‐selective agent, NPC205 (pA₂ = 7.80), further suggests that the contraction is mediated by A₁‐receptors. Moreover, NPC205 was 13 times more potent as an antagonist of R‐PIA‐induced contractions (A₁) than of NECA‐induced relaxations (A₂). The antagonists were also found to relax the trachea by an unknown mechanism. That enprofylline did not antagonize the R‐PIA‐induced contractions, but was 3–4 times more potent a tracheal relaxant than aminophylline, further suggests that a direct effect on airway smooth muscle, rather than antagonism of endogenous adenosine, is more relevant to the bronchodilator effect of alkylxanthines in the treatment of asthma. 1988 British Pharmacological Society