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 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)
Hulsmann
A R
AR
Department of Pediatrics, Erasmus University, Rotterdam, The Netherlands.
Raatgeep
H R
HR
Saxena
P R
PR
Kerrebijn
K F
KF
de Jongste
J C
JC
D000368:Aged; D001713:Biphenyl Compounds / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008875:Middle Aged; D011480:Protease Inhibitors / Q000494:pharmacology; D018002:Receptors, Bradykinin / Q000187:drug effects* / Q000502:physiology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology
D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D006020:Glycopeptides; D006538:Heptanoic Acids; D011480:Protease Inhibitors; D018002:Receptors, Bradykinin; D017482:Receptors, Thromboxane; D016210:Methacholine Chloride; C065679:icatibant; C060013:vapiprost; D001920:Bradykinin; C008890:phosphoramidon; D007213:Indomethacin