Dual and selective antagonism of neurokinin NK1 and NK2 receptor-mediated responses in human colon mucosa

The neurokinin (NK) receptors, NK1 and NK2, which are activated by substance P (SP) and NKA, have been identified as potential therapeutic targets in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here we have investigated the effects of a novel dual NK1 and NK2 receptor antagonist, namely DNK333 upon responses elicited by [Sar(9), Met(O-2)(11)]-SP (SMSP) and [betaAla(8)]-NKA(4-10) in isolated human colon mucosa mounted in Ussing chambers. A selective NK1 receptor antagonist, SR140333 and NK2 receptor antagonist, SR48968 have been tested for comparison. Additions of SMSP (100 nM) or [betaAla(8)]-NKA(4-10) (100 nM) increased basal short-circuit current and responses to both peptides were inhibited by DNK333, while SR140333 only inhibited SMSP and SR48968 blocked only [betaAla(8)]-NKA(4-10) responses. SR140333 did not attenuate [betaAla(8)]-NKA(4-10) effects and SR48968 had no effect upon SMSP responses. Carbachol (1 muM) responses were not altered by any of the three NK antagonists. We conclude that activation of either NK1 or NK2 receptors can stimulate epithelial ion transport in human colon mucosa and that the novel dual antagonist, DNK333 may be of potential therapeutic interest in the treatment of 11313 and IBS.