TACHYKININS CONTRACT TRACHEA FROM FISCHER-344 RATS BY INTERACTION WITH A TACHYKININ NK1 RECEPTOR

The contractile effect of substance P, neurokinin A, carbachol and ser otonin (5-HT) on isolated Fischer 344 rat trachea was studied. Contrac tions 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 X 10(-7) M and ring 2: 2.2 x 10(-7) M) and for 5-HT (EC(50) ring 1: 10.2 X 10(-7) M and ring 2: 10.5 X 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)(X 10(-7) M) of 1.10+/-0.27 and 1.97+/-0.45 respectively. Th e maximal contraction was 32.6+/-2.5% (substance P) and 32.6+/-1.5% (n eurokinin A) of the maximal contraction with carbachol. In contrast, n either substance P nor neurokinin A caused contraction of trachea from BDE rats. The tachykinin NK2 receptor agonist, Ac[Arg(6),Sar(9),Met(O -2)(11)]substance P-(6-11), caused a concentration-dependent contracti on with an EC(50)(X 10(-9) M) of 1.38+/-0.09 and a maximal effect of 2 5.5+/-2.1% of the maximal contraction with carbachol. The tachykinin N K2 receptor agonist, [beta-Ala(8)]neurokinin A-(4-10), had a small con tractile effect at 10(-6) M (8.4+/-0.8% of the maximal contraction wit h carbachol) while the tachykinin NK3 receptor agonist, senktide, had no effect up to 3.3 x 10(-6) M. The tachykinin NK1 receptor antagonist , (+/-)-RP67580 (7,7-diphenyl-2-(1-imino-2-(2-methoxyphenylethyl)- per hydraisoinotol-4-one))) (3 X 10(-9) to 10(-7) M), produced a concentra tion-dependent rightward shift of the concentration-response curve for neurokinin A (Schild plot: slope 1.13, x-intercept 8.4). The tachykin in NK2 receptor antagonist, SR48968 ((S)-N-methyl-N[4-(4-acetylamine-4 -phenyl- piperidino)-2-(3,4-dichlorophenyl) butylbenzamide) (10(-8) to 10(-6) M), had no major effect on the concentration-response for neur okinin A. We conclude that substance P and neurokinin A contract Fisch er 344 rat trachea mainly by interaction with a tachykinin NK1 recepto r.