AR Hulsmann, HR Raatgeep, PR Saxena, KF Kerrebijn and JC de Jongste
Department of Pediatrics, Erasmus University, Rotterdam, The Netherlands.

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 PGE2, PGI2, and TXA2 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 PGE2, PGI2, and TXA2 by the airway tissues were largely inhibited by indomethacin, whereas TTX had no effect. PGE2, PGI2, and TXA2 were released by both intact and epithelium- denuded airways.(ABSTRACT TRUNCATED AT 250 WORDS)

This article has been cited by other articles:

				P. J. Barnes Mediators of Chronic Obstructive Pulmonary Disease Pharmacol. Rev., December 1, 2004; 56(4): 515 - 548. [Abstract] [Full Text] [PDF]

				B.-C. Chen, C.-C. Yu, H.-C. Lei, M.-S. Chang, M.-J. Hsu, C.-L. Huang, M.-C. Chen, J.-R. Sheu, T.-F. Chen, T.-L. Chen, et al. Bradykinin B2 Receptor Mediates NF-{kappa}B Activation and Cyclooxygenase-2 Expression via the Ras/Raf-1/ERK Pathway in Human Airway Epithelial Cells J. Immunol., October 15, 2004; 173(8): 5219 - 5228. [Abstract] [Full Text] [PDF]

				G.F. Joos and B. O'Connor Indirect airway challenges Eur. Respir. J., June 1, 2003; 21(6): 1050 - 1068. [Abstract] [Full Text] [PDF]

				P. J. Barnes, K. F. Chung, and C. P. Page Inflammatory Mediators of Asthma: An Update Pharmacol. Rev., December 1, 1998; 50(4): 515 - 596. [Abstract] [Full Text] [PDF]

				L. Pang, E. Holland, and A. J. Knox Impaired cAMP production in human airway smooth muscle cells by bradykinin: role of cyclooxygenase products Am J Physiol Lung Cell Mol Physiol, August 1, 1998; 275(2): L322 - L329. [Abstract] [Full Text] [PDF]

				L. Pang and A. J. Knox PGE2 release by bradykinin in human airway smooth muscle cells: involvement of cyclooxygenase-2 induction Am J Physiol Lung Cell Mol Physiol, December 1, 1997; 273(6): L1132 - L1140. [Abstract] [Full Text] [PDF]

				F. Nakamura, R. D. Minshall, G. C. Le Breton, and S. F. Rabito Thromboxane A2 Mediates the Stimulation of Inositol 1,4,5-Trisphosphate Production and Intracellular Calcium Mobilization by Bradykinin in Neonatal Rat Ventricular Cardiomyocytes Hypertension, September 1, 1996; 28(3): 444 - 449. [Abstract] [Full Text]