SR 142801, a tachykinin NK(3) receptor antagonist, prevents beta(2)-adrenoceptor agonist-induced hyperresponsiveness to neurokinin A in guinea-pig isolated trachea.
We investigated whether fenoterol was able to enhance contractile responsiveness to neurokinin A (NKA) on the guinea-pig isolated trachea. We then studied the effects of two inhibitors of nuclear factor kappa B (NFkappaB), gliotoxin and pyrrolidine dithiocarbamate, and of the tachykinin NK(1), NK(2) and NK(3) receptor antagonists, SR 140333, SR 48968 and SR 142801 and determined whether tachykinin receptor gene expression was up-regulated in the trachea after exposure to fenoterol. Fenoterol (0.1 microM, 15 h, 21 degrees C) induced an increased contractile response to NKA (mean of difference in maximal tension between control and fenoterol +/- S.E.M; +0.47 +/- 0.14 g, n = 26, P < 0.01). This hyperresponsiveness was strongly reduced by co-incubation with gliotoxin (0.1 microg/ml) or pyrrolidine dithiocarbamate (0.1 mM) and abolished by SR 140333 (0.1 microM) and SR 142801 (0.1 microM). SR 48968 (0.1 microM) diminished the tracheal contractility to NKA but failed to reduce the hyperreactivity induced by fenoterol. Tachykinin NK(1) receptor (NK(1)R), NK(2) receptor (NK(2)R) and NK(3) receptor (NK(3)R) gene expression was analyzed by semiquantitative RT-PCR. Compared to control tissues, NK(1)R and NK(2)R mRNA expression was increased by about 1.6-fold and 1.4-fold, respectively, in tissues treated with fenoterol. We were unable to detect the presence of NK(3)R mRNA in the guinea-pig trachea. In conclusion, fenoterol induces tracheal hyperresponsiveness to NKA and an up-regulation of NK(1)R and NK(2)R gene expression. The hyperresponsiveness implicates the NFkappaB pathway and is abolished by tachykinin NK(1) (SR 140333) and NK(3) (SR 142801) receptor antagonists.
Pinto
F M
FM
Centro de Investigaciones Cienti;ficas Isla de la Cartuja, Instituto de Investigaciones Químicas, 41092 Sevilla, Spain.
Saulnier
J-P
JP
Faisy
C
C
Naline
E
E
Molimard
M
M
Prieto
L
L
Martin
J D
JD
Emonds-Alt
Xavier
X
Advenier
C
C
Candenas
M L
ML
D000109:Acetylcholine / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005280:Fenoterol / Q000037:antagonists & inhibitors*; D005912:Gliotoxin / Q000494:pharmacology; D006168:Guinea Pigs; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D015288:Neurokinin A / Q000494:pharmacology*; D010802:Phylogeny; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013859:Thiocarbamates / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D016328:NF-kappa B; D010880:Piperidines; D011759:Pyrrolidines; D012333:RNA, Messenger; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D013859:Thiocarbamates; D005280:Fenoterol; C020972:pyrrolidine dithiocarbamic acid; D005912:Gliotoxin; D015288:Neurokinin A; C091554:SR 142801; D000109:Acetylcholine