Inhaled adenosine induces bronchoconstriction in asthmatic and allergic subjects but not in nonasthmatics. This study examined the responses of conscious guinea pigs in which antigen sensitization is induced by ovalbumin pretreatment and airway hyperresponsiveness to carbachol is induced by exposure to ozone and platelet-activating factor-acether (PAF). Airway responses to aerosol challenge with carbachol or adenosine were determined as the change in specific airway conductance (SGaw) measured by whole-body plethysmography. In untreated animals, carbachol (20 micrograms/ml, 60 s) induced a rapid fall in SGaw (peak, 18 +/- 5% at 5 min) indicative of bronchoconstriction, whereas adenosine (1 mg/ml, 60 s) caused an increase in SGaw (34 +/- 8% at 15 min). Animals pretreated with ovalbumin displayed similar responses to carbachol (14 +/- 5% at 5 min) as control animals and were therefore sensitized but not hyperresponsive. However, adenosine (1 mg/ml) caused a rapid bronchoconstriction, peaking at 20 min (25 +/- 5%). Exposure of animals to nebulized PAF-acether (10 micrograms/ml) for 60 s produced a bronchoconstriction, which peaked at 10 min (18 +/- 7%) and returned to basal levels by 60 min. Similarly, exposure to ozone (1.4 ppm) for 60 min caused bronchoconstriction (peak at 20 min, 19 +/- 6%), with recovery after 1 h. Both PAF- and ozone-exposed animals displayed significant hyperresponsiveness to carbachol administered 1 h from the end of the exposure period. The peak bronchoconstrictor responses before and after PAF exposure were 10 +/- 9 and 28 +/- 4%, and responses before and after ozone exposure were 22 +/- 5 and 61 +/- 9%.(ABSTRACT TRUNCATED AT 250 WORDS)
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...
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