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

Open Access
Publisher Website
Google Scholar
Abstract
1 The effects of several adenosine analogues and antagonists on guinea-pig isolated trachea have been examined. 2 5′-N-ethylcarboxamidoadenosine (NECA), 5′-N-methylcarboxamidoadenosine (MECA) and adenosine (in the presence and absence of dipyridamole) elicited concentration-dependent tracheal relaxation. 3 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. 4 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. 5 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. 6 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). 7 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.