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 N642-phenylisopropyl)adenosine (R-PIA and S-PIA respectively), N6-cyclohexyladenosine (CHA) and 2-chloroadenosine (CADO) caused contractions at low concentrations (0.05-2.0 yM), 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 A -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.

Effects of NZ-107 on Tracheal Responses to Adenosine in the Guinea Pig.

“…Since the cyclooxygenase inhibitor in domethacin completely inhibited R-PIA-in duced contraction, it is suggested that the con tractile response elicited by R-PIA is mediated by cyclooxygenase metabolites, such as con strictor PGs. Similar results have been re ported by Farmer et al (18) and Caparrotta et al (19). Since NZ-107 (1 ,uM) significantly in hibited the contraction induced by PGF2a, it is suggested that NZ-107 reduces R-PIA-induced contraction by inhibiting the contraction in duced by endogenously released PGF2a.…”

“…The ineffectiveness of AP on forskolin-induced relaxation may be related to the lack of the increase in cAMP at 30 uM. Farmer (18) reported that a xanthine deriva tive, enprofylline, which is not an adenosine antagonist but a potent PDE inhibitor (20), had little effect on R-PIA-induced contraction in the guinea pig trachea. Thus it is unlikely that the inhibitory effect of NZ-107 on Al mediated contraction results from PDE inhibi tion.…”

“…In guinea pig trachea, adenosine-in duced relaxation is reported to be mediated by A2 receptors (16,17). The stable adenosine analogue R-PIA, which is relatively selective for adenosine Al receptors (14), elicits a con tractile response in guinea pig trachea at con centrations lower than about 1 uM (18,19). In the present study, adenosine caused only relaxation at concentrations higher than 3 uM, and R-PIA caused contraction at concentra tions less than 1 u M, suggesting that adeno sine and R-PIA act on A2 and Al receptors, respectively, in the guinea pig trachea.…”

Characterization of P1‐purinoceptors on rat duodenum and urinary bladder

“…Although in several tissues, such as the guinea-pig trachea and aorta, the presence of both subclasses of P1-purinoceptor has been reported, in each case the Al receptor mediates contraction while only the A2 mediates relaxation (Farmer et al, 1988;Stoggall & Shaw, 1990). For two receptor subtypes to mediate the same response in one tissue preparation is unusual, and it is not at all clear why such an apparently redundant system should have evolved.…”

Characterization of P1‐purinoceptors on rat isolated duodenum longitudinal muscle and muscularis mucosae

“…Previous functional studies on the rat duodenum showed that this tissue contained a mixture of Al and A2b receptors both mediating relaxation (Nicholls et al, 1992 ceptor mediated contraction while only the A2 receptor mediated relaxation (Farmer et al, 1988;Stoggall & Shaw, 1990;Bailey & Hourani, 1990; Pharmacology (1996) 117,[170][171][172][173][174] Methods Male Wistar rats, University of Surrey strain, (200-250 g) were killed by cervical dislocation. The duodenum was dissected out by cutting at the base of the pyloris and 1.5 cm from this point, cleared of any connective tissue and placed over a fine bore (diameter: 5 mm) pipette and a longitudinal cut made.…”