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Adenosine receptor‐mediated contraction and relaxation of guinea‐pig isolated tracheal smooth muscle: effects of adenosine antagonists
Author(s) -
Farmer Stephen G.,
Canning Brendan J.,
Wilkins Deidre E.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11655.x
Subject(s) - adenosine , adenosine receptor , adenosine receptor antagonist , contraction (grammar) , aminophylline , chemistry , medicine , endocrinology , muscle contraction , antagonist , adenosine a1 receptor , receptor , biology , agonist
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 N 6 ‐(2‐phenylisopropyl)adenosine ( R ‐PIA and S‐PIA respectively), N 6 ‐cyclohexyladenosine (CHA) and 2‐chloroadenosine (CADO) caused contractions at low concentrations (0.05–2.0 μ m ), 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 A 2 ‐receptors, whereas contraction is the result of activation of A 1 ‐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 A 1 ‐selective agent, NPC205 (pA 2 = 7.80), further suggests that the contraction is mediated by A 1 ‐receptors. Moreover, NPC205 was 13 times more potent as an antagonist of R ‐PIA‐induced contractions (A 1 ) than of NECA‐induced relaxations (A 2 ). 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.