Desensitization of the peristaltic reflex induced by mucosal stimulation with the selective 5-HT4 agonist tegaserod.
The intestinal peristaltic reflex induced by mucosal stimulation is mediated by mucosal release of serotonin (5-HT), which acts on 5-HT(4) receptors located on CGRP-containing afferent nerve terminals. Exposure of the colonic mucosa to the 5-HT(4) receptor agonist tegaserod in the range of 1 nM to 10 muM elicits a peristaltic reflex and stimulates colonic propulsion. The present study was designed to identify the 5-HT(4) receptor subtype mediating the reflex and determine whether functionally effective concentrations of tegaserod desensitize the reflex induced by mucosal stimulation. Exposure of rat colonic mucosa to tegaserod in the range of 5 nM to 5 muM for 5 or 10 min caused rapid time- and concentration-dependent desensitization of the peristaltic reflex induced by mucosal stroking, consistent with the operation of a rapidly desensitizing 5-HT(4b) receptor subtype. Desensitization was accompanied by a decrease in CGRP release. The rate of recovery of peristaltic response depended on the desensitizing concentration of tegaserod: ascending contraction and descending relaxation recovered within 15 min after 5-50 nM tegaserod, 30 min after 0.5 muM, and 60 min after 5 muM. Neither CGRP release nor the peristaltic reflex induced by muscle stretch was affected by 5-HT(4) receptor desensitization, providing further evidence that 5-HT does not mediate the reflex induced by muscle stretch. These results suggest in cases of increased 5-HT availability or prolonged exposure, such as colitis, that it is likely the peristaltic reflex will be blunted.
Grider
John R
JR
Department of Physiology, PO Box 980551, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA. jgrider@hsc.vcu.edu
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D010528:Peristalsis / Q000187:drug effects*; D010812:Physical Stimulation; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013268:Stimulation, Chemical
D007211:Indoles; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; C105050:tegaserod; D015740:Calcitonin Gene-Related Peptide