Vol. 280, Issue 4, C852-C858, April 2001
Potent NK1 antagonism by SR-140333 reduces rat
colonic secretory response to immunocyte activation
Derek
Moriarty1,
Norma
Selve2,
Alan W.
Baird1,3, and
Jon
Goldhill2
1 Department of Veterinary Physiology and Biochemistry and
3 Conway Institute of Biomolecular and Biomedical Research,
University College Dublin, Belfield, Dublin 4, Ireland; and
2 Department of Internal Medicine, Sanofi-Synthélabo,
92504 Rueil-Malmaison, France
The potent
neurokinin receptor 1 (NK1) antagonist SR-140333
has previously been shown to reduce castor oil-induced secretion in
animal models. The importance of tachykinins in neuroimmune control of
secretion and the effect of SR-140333 on key points in this pathway
were elucidated in the present study to determine the type of
intestinal dysfunction best targeted by this antagonist. Rat colonic
secretion and substance P (SP) release were determined in vitro with
the use of Ussing chamber and enzyme immunoassay techniques.
NK1 receptors played a secretory role as receptor agonists
stimulated secretion and SR-140333 antagonized the response to SP
response (pKb = 9.2). Sensory fiber stimulation
released SP and evoked a large secretion that was reduced by 69% in
the presence of SR-140333 (10 nM). Likewise, mastocytes also released SP. The subsequent secretory response was reduced by 43% in the presence of SR-140333 (50 nM). SP was also released from granulocytes; however, this did not cause secretion. Functional NK3
receptors were present in the colon as senktide stimulated secretion,
an effect that was increased during stress. We conclude that
NK3 receptors may play a role in stress-related disorders,
whereas NK1 receptors are more important in mast
cell/afferent-mediated secretion.
afferent; granulocyte; irritable bowel syndrome; inflammatory bowel
disease; mast cell
