title: Adenosine receptor-mediated contraction and relaxation of guinea-pig isolated tracheal smooth muscle: effects of adenosine antagonists.
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 microM), whereas at higher concentrations, relaxation resulted. 4. For tracheal relaxation, the adenosine analogues exhibited the following rank order of potency: NECA greater than CADO greater than R-PIA = MECA greater than S-PIA greater than adenosine. The rank order of potency for inducing contractions was R-PIA greater than CHA greater than CADO greater than 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.
authors.affiliation: Nova Pharmaceutical Corporation, Baltimore, Maryland 21224.
authors.forename: S G
authors.initials: SG
authors.lastname: Farmer
authors.forename: B J
authors.initials: BJ
authors.lastname: Canning
authors.forename: D E
authors.initials: DE
authors.lastname: Wilkins
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D004176:Dipyridamole / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000502:physiology*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; C046756:5'-N-methylcarboxamideadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C027513:N(6)-cyclohexyladenosine; D004176:Dipyridamole; D000241:Adenosine