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 the rat isolated distal colon, respectively. The tachykinin NK2 receptor-selective antagonist nepadutant (c(([(β-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2β-5β))) produced competitive antagonism of [βAla8]neurokinin A-(4-10)-induced contraction (pKB = 9.3) in the muscularis mucosae, and insurmountable blockade of increases in short-circuit current (Isc) responses (pKB = 8.6) in the mucosa. However, this latter effect was completely reversed by washout of the antagonist. [βAla8]Neurokinin A-(4-10)-induced contractions were unaffected by indomethacin (3 μM). In sharp contrast, Isc responses induced by [βAla8]neurokinin A-(4-10) (100 nM) were inhibited (> 70%) by indomethacin (3 μM), while Isc responses to substance P (3 μM) were unchanged. Our study provides the first evidence that in the same organ stimulation of tachykinin NK2 receptors leads to two independent responses mediated by different effector mechanisms both of which are blocked (albeit with different kinetics) by the potent and selective tachykinin NK2 receptor antagonist, nepadutant. © 2001 Elsevier Science B.V.