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 rats is accompanied by release into the airways of 5-hydroxytryptamine (5-HT). 5-HT is possibly derived from mast cells. In the present study the presumed mast cell-tachykinin interaction was studied in isolated trachea from Fisher 344 rats. Contractions induced by neurokinin A were largely reduced by the 5-HT antagonist methysergide, partially reduced by atropine, but not affected by hexamethonium or tetrodotoxin. Methysergide also inhibited the contractions induced by substance P, the tachykinin NK1 receptor agonist Ac[Arg(6), Sar(9), Met(O-2)(11)]substance P-(6-11) and the mast cell depleting compound 48/80. Methysergide had no effect on contractions induced by carbachol or electrical field stimulation. Atropine significantly reduced contractions to 5-HT and completely inhibited contractions induced by electrical field stimulation. Histamine had no contractile effect. In vivo pretreatment with compound 48/80 significantly reduced the in vitro contractions to neurokinin A. Contractions to capsaicin were inhibited by methysergide and the tachykinin NK1 receptor antagonist (+/-)-RP67580 ((3aR,7aR)-(7,7-diphenyl-2-(1-imino-2-(2-methoxyphenylethyl)-perhydraisoinotol-4-one))). Substance P and neurokinin A caused 5-HT release in the organ bath, in a concentration-and time-dependent way. Atropine did not affect 5-HT release. Morphometric analysis showed that substance P and neurokinin A, but not carbachol, caused a significant increase in the number of degranulating mast cells in the muscular/submuscular region. In conclusion, tachykinins contract Fisher 344 rat trachea by releasing 5-HT from mast cells, an effect mediated by a tachykinin NK1 receptor. (C) 1997 Elsevier Science B.V.