Tachykinin NK2 receptor mediates contraction and ion transport in rat colon by different mechanisms

We have characterized the tachykinin NK2 receptor-mediated contraction and vectorial ion transport responses in the muscularis mucosae and mucosa of t he rat isolated distal colon, respectively. The tachykinin NK2 receptor-sel ective antagonist nepadutant (c{[(beta -D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c( 2 beta -5 beta)}) produced competitive antagonism of [beta Ala(8)]neurokini n A-(4-10)-induced contraction (pK(B) = 9.3) in the muscularis mucosae, and insurmountable blockade of increases in short-circuit current (I-sc) respo nses (pK(B) = 8.6) in the mucosa. However, this latter effect was completel y reversed by washout of the antagonist. [beta Ala(8)]Neurokinin-A A-(4-10) -induced contractions were unaffected by indomethacin (3 muM). In sharp con trast, I-sc responses induced by [beta Ala(8)]neurakinin A-(4-10) (100 nM) were inhibited (> 70%) by indomethacin (3 muM), while I,, responses to subs tance P (3 muM) were unchanged. Our study provides the first evidence that in the same organ stimulation of tachykinin NK, receptors leads to two inde pendent responses mediated by different effector mechanisms both of which a re blocked (albeit with different kinetics) by the potent and selective tac hykinin NK, receptor antagonist, nepadutant. (C) 2001 Elsevier Science B.V. All rights reserved.