BRADYKININ-INDUCED CONTRACTION OF HUMAN PERIPHERAL AIRWAYS MEDIATED BY BOTH BRADYKININ BETA(2) AND THROMBOXANE PROSTANOID RECEPTORS

Bradykinin (BK) induces bronchoconstriction in asthmatic but not in normal individuals. Studies in vivo in the human suggest that BK causes cholinergic nerve activation, release of prostanoids, and local axon reflexes with release of tachykinins in the airways. To determine the mechanisms of BK-induced airway narrowing, we investigated the effects of epithelium removal, inhibition of the enzymes neutral endopeptidase (NEP) and cyclooxygenase, and blockade of neural conductance with tetrodotoxin (TTX) on BK-induced responses of human isolated peripheral airways. Responses to BK were recorded from airways with spontaneous intrinsic tone and from airways precontracted with methacholine. Furthermore, we measured the BK-induced release of the prostanoids PGE(2), PGl(2), and TXA(2) from airways with and without epithelium in the absence and presence of indomethacin by radioimmunoassay. Finally, we examined the effect of the bradykinin beta(2) receptor antagonist Hoe 140 and the thromboxane prostanoid (TP) receptor blocking drug GR32191 on BK-induced responses. BK contracted intact and epithelium-denuded airways with spontaneous intrinsic tone, whereas precontracted airways either relaxed or contracted to BK. Removal of the epithelium increased the sensitivity to BK sevenfold without changing the direction of the response. The NEP inhibitor phosphoramidon tended to increase the sensitivity to BK (NS) and did not change the direction of the response. Both contractile and relaxation responses to BK and the release of the prostanoids PGE(2), PGl(2), and TXA(2) by the airway tissues were largely inhibited by indomethacin, whereas TTX had no effect. PGE(2), PGl(2), and TXA(2) were released by both intact and epithelium-denuded airways. BK-induced responses were antagonized by both Hoe 140 and GR32191. It is concluded that BK is a potent constrictor of human peripheral airways, especially in the absence of epithelium. Involvement of local axon reflexes with release of tachykinins could not be demonstrated. The effect of BK on human airway smooth muscle is mediated via the beta(2) receptor and involves the release of prostanoids that contract airways via the TP receptor.