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

Abstract

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...

Airway hyper‐ or hyporeactivity to inhaled spasmogens 24 h after ovalbumin challenge of sensitized guinea‐pigs

“…Isolated bronchi from asthmatic subjects show a contractile response which is thought to be mediated indirectly by liberation of leukotrienes and histamine (Bj6rck et al, 1992). Similarly, isolated lung tissues from sensitized guinea-pigs show a constrictor response to adenosine whereas tissues from unsensitized animals display the more usual direct smooth muscle relaxant effects mediated via A2 receptors (Thorne & Broadley, 1992). The bronchoconstrictor responses to adenosine or 5'-AMP in whole animals (Thorne & Broadley, 1994) human subjects (Phillips et al, 1989) and isolated tissues (Thorne & Broadley, 1992) are rapidly tachyphylactic.…”

Purinergic Signaling in the Airways

“…Inflammatory mediators inhibited by indomethacin may be involved in adenosine bronchoconstriction (Crimi et al, 1989). In perfused lungs sensitized with ovalbumin, adenosine produced bronchoconstriction, but at high concentrations, it had bronchodilator actions (Thorne and Broadley, 1992). The ADP receptor antagonist 8-phenyltheophylline blocked relaxant but not contractile responses.…”

Strain-Related Differences in the Tracheal Responsiveness of Sensitized Guinea Pig

“…Previous studies using sensitized guinea pigs have reported conflicting results. Some failed to demonstrate a nonspecific increase in re sponsiveness to bronchoconstrictors applied in vitro, before any antigen challenge [21][22][23][24]. Nevertheless, such a typical nonspecific hyperreactivity has been observed in many oth er studies [25][26][27][28].…”