Tachykinins contract trachea from Fischer 344 rats by interaction with a tachykinin NK 1 receptor

Abstract

The contractile effect of substance P, neurokinin A, carbachol and serotonin (5-HT) on isolated Fischer 344 rat trachea was studied. Contractions of two distal tracheal rings were measured isometrically in a 2-ml organ bath. Cumulative concentration-response curves were obtained for carbachol (EC 50 ring 1:1.6 × 10 −7 M and ring 2:2.2 × 10 −7 M) and for 5-HT (EC 50 ring 1: 10.2 × 10 −7 M and ring 2:10.5 × 10 −7 M). Non-cumulative administration of substance P and neurokinin A (10 −8 to 10 −5 M) caused a concentration-dependent contraction with an EC 50(× 10 −7 M) of 1.10 ± 0.27 and 1.97 ± 0.45 respectively. The maximal contraction was 32.6 ± 2.5% (substance P) and 32.6 ± 1.5% (neurokinin A) of the maximal contraction with carbachol. In contrast, neither substance P nor neurokinin A caused contraction of trachea from BDE rats. The tachykinin NK 1 receptor agonist, Ac[Arg 6, Sar 9, Met(O 2) 11]substance P-(6–11), caused a concentration-dependent contraction with an EC 50(× 10 −9M) of 1.38 ± 0.09 and a maximal effect of 25.5 ± 2.1% of the maximal contraction with carbachol. The tachykinin NK 2 receptor agonist, [β-Ala 8]neurokinin A-(4–10), had a small contractile effect at 10 −6 M (8.4 ± 0.8% of the maximal contraction with carbachol) while the tachykinin NK 3 receptor agonist, senktide, had no effect up to 3.3 × 10 −6 M. The tachykinin NK 1 receptor antagonist, (±)-RP67580 ((3 aR, 7 aR)-(7,7-diphenyl-2-(1-imino-2-(2-methoxyphenylethyl)-perhydraisoinotol-4-one))) (3 × 10 −9 to 10 −7 M), produced a concentration-dependent rightward shift of the concentration-response curve for neurokinin A (Schild plot: slope 1.13, x-intercept 8.4). The tachykinin NK 2 receptor antagonist, SR48968 (( S)- N-methyl- N[4-(4-acetylamine-4-phenylpiperidino)- 2-(3,4-dichlorophenyl) butylbenzamide) (10 −8 to 10 −6 M), had no major effect on the concentration-response for neurokinin A. We conclude that substance P and neurokinin A contract Fischer 344 rat trachea mainly by interaction with a tachykinin NK 1 receptor.