Theophylline

1 The bronchoconstriction of airway-perfused lungs and contraction of superfused tracheal spirals from guinea-pigs in response to adenosine were examined. 2 In lungs from untreated animals, adenosine had little effect unless the perfusion pressure was raised with carbachol (1.1 tlM), when it caused a fall in perfusion pressure. However, if removed from guinea-pigs sensitized with ovalbumen (5 mg and 10 mg i.p. 14 and 12 days before use), adenosine was bronchoconstrictor, exerting bronchodilator effects only at high (1 mg) doses. The constrictor response to adenosine (300 lig) was significantly greater than that in lungs from untreated or sham-injected animals. 3 In superfused trachea from untreated animals, adenosine exerted only relaxant responses. In tissues from ovalbumen-sensitized guinea-pigs adenosine produced contracile responses, with relaxation appearing only at high (1 mg) doses. 4 Thus sensitization by antigen challenge revealed a bronchoconstrictor response of isolated airway preparations to adenosine. This is related to the clinical situation where only asthmatic subjects respond to adenosine by bronchoconstriction and suggests that the sensitization may destabilize inflammatory cells for mediator release by adenosine. 5 The response to a second exposure to adenosine was consistently reduced (lungs) or converted to a relaxation (trachea) indicating tachyphylaxis and consistent with a mediator release mechanism. 6 The P,-purinoceptor antagonist, 8-phenyltheophylline (3.9 jiM), antagonized the relaxant responses to higher doses of adenosine. However, it did not affect the contractile responses to lower doses of adenosine. Whether this is due to P,-purinoceptors not being involved in the contractile response, or whether preferential blockade of the relaxant response leaves the contraction unopposed and apparently unblocked, remains to be established. Keywords: Adenosine; airway perfused lungs of guinea-pig; superfused trachea; bronchoconstriction; ovalbumen sensitization IntroductionThe predominant response of airway smooth muscle to adenosine is relaxation (Farmer & Farrar, 1976;Karlsson et al., 1982;Darmani & Broadley, 1986) which is mediated via P,-purinoceptors of the A2-subtype (Brown & Collis, 1982). In human non-asthmatic subjects, however, adenosine has no effect upon pulmonary function (Cushley et al., 1983) while in asthmatics it produces a bronchoconstriction (Cushley et al., 1983;Crimi et al., 1988;1989 (Satchell & Smith, 1984). The small contractile component precedes the predominant relaxation (Coleman, 1976;Karlsson et al., 1982) and appears to depend upon the degree of resting tone (Fredholm et al., 1979;Advenier et al., 1982). There is some Author for correspondence. disagreement regarding whether the contractile response to the adenosine analogue L-N6-phenylisopropyladenosine (L-P1A) is antagonized by PI-receptor antagonists (Caparrotta et al., 1984;Ghai et al., 1987;Farmer et al., 1988). However, the possibility exists for it being mediated via the release of arachidonic acid derivat...

Section: Discussioncontrasting

confidence: 95%

Adenosine‐induced bronchoconstriction of isolated lung and trachea from sensitized guinea‐pigs

Thorne

Broadley

1992

“…Thus, nonmetabolizable PI purinoceptor agonists might be useful therapeutically in treatment of CF. It should be noted, however, that while ADO does not induce bronchoconstriction in normal subjects, it enhances bronchoconstriction in asthmatic patients (Cushley et al, 1984). This side-effect of ADO can be attenuated by nedocromil sodium and sodium cromoglycate (Crimi et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of chloride secretion by P₁ purinoceptor agonists in cystic fibrosis phenotype airway epithelial cell line CFPEo‐

Chao

Zifferblatt

Wagner

et al. 1994

1 P1 purinoceptor agonists like adenosine have been shown to stimulate Cl-transport in secretory epithelia. In the present study, we investigated whether P1 agonist-induced Cl-secretion is preserved in cystic fibrosis airway epithelium and which signalling mechanism is involved. The effects of purinoceptor agonists on Cl-secretion were examined in a transformed cystic fibrosis airway phenotype epithelial cell line, CFPEo-. 2 Addition of adenosine (ADO; 0.1-1 mM) markedly increased 1251 efflux rate. The rank order of potency of purinoceptor agonists in stimulating 1251I efflux was ADO>AMP>ADP-ATP. A similar order of potency was seen in transformed cystic fibrosis nasal polyp cells, CFNPEo-(ADO>ATP > AMP> ADP). These results are consistent with the activation of Cl-secretion via a P1 purinoceptor. 3 The P1 agonists tested (at 0.01 and 0.1 mM) revealed a rank order of potency of 5'-Nethylcarboxamine adenosine (NECA)>2-chloro-adenosine (2-Cl-ADO)>R-phenylisopropyl adenosine (R-PIA). 4 The known potent A2 adenosine receptor (A2AR) agonist, 5'-(N-cyclopropyl) carboxamidoadenosine (CPCA, 2 JiM) but not the A1 adenosine receptor agonist, N6-phenyl adenosine (N6-phenyl ADO, 10 ELM) markedly increased 1251 efflux rate (baseline, 5.9 ± 2.0% min-', + CPCA, 10.9 ± 0.6% min-'; P<0.01). The stimulant effect of CPCA (10 gLM) was abolished by addition of the A2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (100 ,.m; reported Ki = 11 ± 3 fiM). These results favour the involvement of A2AR. 6 In patch-clamp experiments, ADO (1 mM) induced an outwardly-rectified whole-cell Cl-current (baseline, 2.5 ± 0.8 pA pF-, + ADO, 78.4 ± 23.8 pA pF-'; P<0.02), which was largely inhibited in cells internally perfused with a selective inhibitory peptide of the multifunctional Ca2+/calmodulindependent protein kinase, CaMK (20 gM), as compared to a control peptide, CaMK [284][285][286][287][288][289][290][291][292][293][294][295][296][297][298][299][300][301][302]. Addition of BAPTA (10 mM), a Ca2+ chelator, to the perfusion pipette also abolished the ADO-elicited Cl-current. 7 In conclusion, our results suggest that A2AR participates in regulation of airway C1 secretion via a Ca2+-dependent signalling pathway, which involves CaMK and appears to be at least partially conserved in cystic fibrosis airway epithelial cells.

“…Although allergic non-asthmatics bronchoconstrict when exposed to adenosine, they do so to a lesser degree than atopic asthmatics, and normal subjects show little or no response (Cushley et al, 1983). Dipyridamole, an inhibitor of adenosine uptake, enhances adenosine-induced bronchospasm in asthmatics when administered intravenously or by inhalation (Crimi et al, 1988), an effect that can be inhibited by theophylline, an adenosine receptor antagonist (Cushley et al, 1984). This suggests that there may be increased expression of adenosine receptor(s) in asthmatic airways.…”

Section: Introductionmentioning

confidence: 99%

Characterization of adenosine receptors involved in adenosine‐induced bronchoconstriction in allergic rabbits

El-Hashim

D’Agostino

Matera

et al. 1996

1 Recent work has suggested that adenosine may be involved in asthma via the activation of A1 receptors. However, the role of the recently cloned A3 receptor in airways is largely unknown. In the present study, we have investigated the role of the A3 receptor in adenosine-induced bronchoconstriction in allergic rabbits. 2 Aerosol challenge of antigen (Ag) immunized rabbits with the adenosine precursor, adenosine 5'-monophosphate (AMP), resulted in a dose-dependent fall in dynamic compliance (Cdyn). The maximum fall in Cdyn in these rabbits was significantly greater than that in litter matched, sham immunized animals (P<0.05). However, there was no significant difference in the maximum increase in airways resistance (RL) between Ag and sham immunized rabbits (P>0.05).3 Aerosol challenge of Ag immunized rabbits with cyclopentyl-adenosine (CPA) (Al-receptor agonist) elicited a dose-dependent fall in Cdyn in Ag immunized rabbits and the maximum fall in Cdyn in these rabbits was significantly greater than that observed in sham immunized rabbits (P<0.05). Similarly, CPA induced dose-dependent increases in RL in Ag immunized rabbits whereas sham immunized rabbits failed to respond to CPA within the same dose range. The maximum increase in RL in Ag immunized rabbits was significantly greater than that of sham immunized rabbits (P<0.05). 4 Aerosol challenge of either Ag or sham immunized rabbits with the A3 agonist aminophenylethyladenosine (APNEA) did not elicit dose-dependent changes in either RL or Cdyn. Moreover, there was no significant difference in the maximum response, measured by either parameter, between the two animal groups (P>0.05).5 These data provide further evidence for a role of the Al receptor in the airways, but do not support a role for the A3 receptor in adenosine-induced bronchoconstriction in the allergic rabbit.