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1. Bradykinin (BK) is a nine amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) formed from the plasma precursor kininogen during inflammation and tissue injury. The actions of BK are mediated by G protein-coupled cell surface receptors, designated B1 and B2. 2. BK has a plethora of effects in the airways including bronchoconstriction, bronchodilation, stimulation of cholinergic and sensory nerves, mucus secretion, cough and oedema resulting from promotion of microvascular leakage. These airway effects are mediated in the main by the B2 receptor subtype. 3. BK acts mainly indirectly, primarily through airway nerve activation, but also by the release of prostanoids, thromboxanes and nitric oxide (NO). 4. Airway responses to BK have been studied in detail in guinea-pigs, mice, sheep and rats. This review describes the effects of BK in these species and draws comparison with its effects in normal humans and patients with respiratory diseases. 5. Despite its many and varied effects in the airways of animals and man, the exact contribution of BK to airways disease remains unclear.

The mechanism(s) of bradykinin-induced bronchoconstriction was investigated in the Brown Norway (BN) rat model of allergic asthma. Bronchoconstrictor responses to i.v. bradykinin in BN rats were maximally augmented 24 h following challenge with allergen and declined at later time points. Histological evaluation of the inflammatory status of the lungs after ovalbumin (OA) challenge showed a marked inflammatory response, which was maximal at 24 h and declined thereafter. However, pretreatment with budesonide did not inhibit the augmented bronchoconstrictor response to bradykinin 24 h after allergen challenge. The selective B1 receptor agonist, Lys-[desArg9]-BK had no bronchoconstrictor effects, whereas the selective B2 receptor antagonist, HOE 140, abolished the response to bradykinin in OA-challenged animals. The augmented response to bradykinin was not affected by methysergide, indomethacin, disodium cromoglycate, iralukast, the 5-lipoxygenase inhibitor, CGS8515, or the NK2 receptor antagonist, SR48968. It was, however, partially inhibited by atropine both in saline- and OA-challenged animals. Pretreatment with captopril and thiorphan markedly potentiated responses to bradykinin both in saline- and OA-challenged animals. Thus, augmentation of the bronchoconstrictor response to bradykinin occurs in actively sensitised BN rats 24 h after challenge with OA and is associated with marked pulmonary inflammation. The response is entirely B2 receptor mediated and approximately 50% of the response is cholinergic. However, mast cell activation, the products of the cyclooxygenase or 5-lipoxygenase pathways and tachykinins are not involved. Peptidase inhibition mimics the effect of allergen challenge on the bronchoconstrictor response to bradykinin and it remains possible that the mechanism of the augmented response to bradykinin following allergen challenge involves downregulation of peptidase activity as a consequence of the inflammatory response.

1 Endogenous adenosine has been suggested to amplify the response of airway mast cells to allergen in vivo. We have sought evidence for this by monitoring the acute and late-phase response to allergen in Brown Norway (BN) rats actively sensitised to ovalbumin (OA) and treated either with adenosine deaminase (ADA) linked covalently to polyethylene glycol (PEG-ADA; Adagen s ) to decrease adenosine availability or with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor of ADA, plus S-(4-nitrobenzyl)-6-thioinosine (NBTI), an inhibitor of facilitated adenosine transport, to increase adenosine availability. 2 The cardiovascular effects of adenosine (0.01 -3 mg kg À1 i.v.) were significantly reduced in PEG-ADA-treated animals and augmented in EHNA/NBTI-treated animals. The difference in sensitivity to adenosine in the treated groups was 33-and 15-fold, at the level of 30% reduction in blood pressure and heart rate, respectively. 3 The acute response to allergen, given either intravenously or intratracheally, was quantified as bronchoconstriction. The late phase to allergen was measured as the influx and activation of immunoinflammatory cells into the bronchoalveolar lavage fluid 24 h after challenge. 4 Despite evidence of a substantial difference in adenosine availability following pretreatment with PEG-ADA or EHNA/NBTI, there were no differences in either the acute or late response to allergen in the actively sensitised BN rat. 5 Our data suggest no role for endogenous adenosine in determining the response to allergen under our experimental conditions.

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