The aim of this study was to examine the integrative response to neurokinin A (NKA) on duodenal mucosal permeability, bicarbonate secretion, fluid flux, and motility in an in situ perfusion model in anesthetized rats. Intravenous infusion of NKA (100, 200, and 400 pmol.kg-1.min-1) induced duodenal motility. Furthermore, duodenal mucosal bicarbonate secretion, fluid output, and mucosal permeability increased in response to NKA. Pretreatment with the nicotinic antagonist hexamethonium did not change the response in any of the parameters investigated, whereas the NK2-receptor antagonist MEN 10,627 effectively inhibited all responses to NKA. Indomethacin induced duodenal motility and stimulated bicarbonate secretion. In indomethacin-treated rats, NKA further increased motility but decreased indomethacin-stimulated bicarbonate secretion by 70%. The NKA-induced increase in mucosal permeability was unaltered by indomethacin. It is concluded that NKA not only induces motility but also increases mucosal permeability and fluid output. Furthermore, the neuropeptide may have both stimulative and inhibitory effects on bicarbonate secretion. All responses to NKA are dependent on NK-2 receptor activation but are not mediated through nicotinic receptors.