ROLE OF 5-HYDROXYTRYPTAMINE AND MAST-CELLS IN THE TACHYKININ-INDUCED CONTRACTION OF RAT TRACHEA IN-VITRO

The in vivo bronchoconstrictor effect of tachykinins in Fisher 344 rat s is accompanied by release into the airways of 5-hydroxytryptamine (5 -HT). 5-HT is possibly derived from mast cells. In the present study t he presumed mast cell-tachykinin interaction was studied in isolated t rachea from Fisher 344 rats. Contractions induced by neurokinin A were largely reduced by the 5-HT antagonist methysergide, partially reduce d by atropine, but not affected by hexamethonium or tetrodotoxin. Meth ysergide also inhibited the contractions induced by substance P, the t achykinin NK1 receptor agonist Ac[Arg(6), Sar(9), Met(O-2)(11)]substan ce P-(6-11) and the mast cell depleting compound 48/80. Methysergide h ad no effect on contractions induced by carbachol or electrical field stimulation. Atropine significantly reduced contractions to 5-HT and c ompletely inhibited contractions induced by electrical field stimulati on. Histamine had no contractile effect. In vivo pretreatment with com pound 48/80 significantly reduced the in vitro contractions to neuroki nin A. Contractions to capsaicin were inhibited by methysergide and th e tachykinin NK1 receptor antagonist (+/-)-RP67580 (2-methoxyphenyleth yl)-perhydraisoinotol-4-one))). Substance P and neurokinin A caused 5- HT release in the organ bath, in a concentration-and time-dependent wa y. Atropine did not affect 5-HT release. Morphometric analysis showed that substance P and neurokinin A, but not carbachol, caused a signifi cant increase in the number of degranulating mast cells in the muscula r/submuscular region. In conclusion, tachykinins contract Fisher 344 r at trachea by releasing 5-HT from mast cells, an effect mediated by a tachykinin NK1 receptor. (C) 1997 Elsevier Science B.V.