Human colonic anti-secretory activity of the potent NK(1) 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 stimuli 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 stimulation (1 ms/7 Hz/7 V) and capsaicin (50 microM) respectively, mast cell activation by anti-IgE (1/250 dilution) and granulocyte stimulation using fMLP (50 microM) each released SP and evoked a secretory response. 3. SP and the NK(1) selective agonist, Sar-SP (0.1 - 1000 nM) stimulated an increase 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 NK(1)-mediated secretion (500 nM), also reduced the secretory response to both alphaIgE and capsaicin. This suggests a pathophysiologic role for NK(1) receptors. 5. Capsaicin evoked SP release was increased in tissue taken from Crohn's disease but not ulcerative colitis patients. The response to SP was however reduced 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 stimulation this compound may be particularly useful in reducing the symptoms of food allergy.
Moriarty
D
D
Department of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland.
Goldhill
J
J
Selve
N
N
O'Donoghue
D P
DP
Baird
A W
AW
D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology / Q000627:therapeutic use*; D002211:Capsaicin / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005512:Food Hypersensitivity / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015287:Neurokinin B / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use*; D011812:Quinuclidines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013045:Species Specificity; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015320:Tachykinins / Q000819:agonists / Q000378:metabolism
D000930:Antidiarrheals; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; C085215:SR 140333; D013373:Substance P; D007073:Immunoglobulin E; D015288:Neurokinin A; D015287:Neurokinin B; D002211:Capsaicin