Effect of nepadutant at tachykinin NK 2 receptors in human intestine and urinary bladder

Abstract

We have characterized the action of the tachykinin NK 2 receptor antagonist nepadutant (c{[(β- d-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2β–5β)}) in the human isolated ileum, colon and urinary bladder. Nepadutant (30–1000 nM) competitively antagonized neurokinin A- or [βAla 8]neurokinin A-(4–10)-induced contractions in all tissues, with p K B=8.3 (ileum and colon) and p K B=8.5 (bladder). In contrast, the nonpeptide tachykinin NK 2 receptor antagonist SR 48968 (or ( S)- N-methyl- N [4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl] benzamide) (30–1000 nM) produced insurmountable antagonism in all preparations. The tachykinin NK 2 receptor blockade produced by nepadutant in the colon was fully reversed by washout, whereas that produced by SR 48968 was not. Nepadutant (1 μM) greatly reduced (by 70–80%) the nonadrenergic noncholinergic (NANC) contractile off-response evoked by electrical field stimulation in the human ileum, and almost abolished it in the presence of the tachykinin NK 1 receptor antagonist GR 82334 (or: [[( S, S) Pro-Leu (spiro-γ-lactam)] 9,10,Trp 11]Physalaemin (1–11)) (1 μM). The present results show that nepadutant is a potent, competitive and reversible antagonist at human tachykinin NK 2 receptors and provide further evidence that tachykinins act as excitatory NANC neurotransmitters in the human small intestine.