Human colonic anti-secretory activity of the potent NK1 antagonist, SR140333: assessment of potential anti-diarrhoeal activity in food allergy and inflammatory bowel disease

1 This in vitro study was designed to determine the potential use of the NK 1 antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimu li on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated. 2 Submucosal and sensory nerve fibre stimulation using electrical field sti mulation (1 ms/7 Hz/7 V) and capsaicin (50 muM) respectively, mast cell act ivation by anti-IgE (1/250 dilution) and granulocyte stimulation using FMLP (50 muM) each released SP and evoked a secretory response. 3 SP and the NK1 selective agonist, Sar-SP (0.1- 1000 nM) stimulated an inc rease in colonic secretion which was antagonized by SR140333 (pD'(2) = 6.7 and 7.25 versus SP and Sar-SP respectively). 4 SR140333, at a concentration that blocked NK1-mediated secretion (500 nM) , also reduced the secretory response to both alpha IgE and capsaicin. This suggests a pathophysiologic role for NK1 receptors. 5 Capsaicin evoked SP release was increased in tissue taken from Crohn's di sease but not ulcerative colitis patients. The response to SP was however r educed by 70 and 89% respectively. 6 Mast cells and sensory afferents contribute to allergic diarrhoea. Since SR140333 reduced the secretory response to mast cell and afferent stimulati on this compound may be particularly useful in reducing the symptoms of foo d allergy.