Neurogastroenterology of tegaserod (HTF 919) in the submucosal division of the guinea‐pig and human enteric nervous system

Abstract

Actions of the 5-HT(4) serotonergic receptor partial agonist, tegaserod, were investigated on mucosal secretion in the guinea-pig and human small intestine and on electrophysiological behaviour of secretomotor neurons in the guinea-pig small intestinal submucosal plexus. Expression of 5-HT(4) receptor protein and immunohistochemical localization of the 5-HT(4) receptor in the submucosal plexus in relation to expression and localization of choline acetyltransferase and the vesicular acetylcholine (ACh) transporter were determined for the enteric nervous system of human and guinea-pig small intestine. Immunoreactivity for the 5-HT(4) receptor was expressed as ring-like fluorescence surrounding the perimeter of the neuronal cell bodies and co-localized with the vesicular ACh transporter. Exposure of mucosal/submucosal preparations to tegaserod in Ussing chambers evoked increases in mucosal secretion reflected by stimulation of short-circuit current. Stimulation of secretion had a relative high EC(50) of 28.1 +/- 1.3 mumol L(-1), was resistant to neural blockade and appeared to be a direct action on the secretory epithelium. Tegaserod acted at presynaptic 5-HT(4) receptors to facilitate the release of ACh at nicotinic synapses on secretomotor neurons in the submucosal plexus. The 5-HT(2B) receptor subtype was not involved in actions at nicotinic synapses or stimulation of secretion.

Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea

“…These methods were essentially the same as described previously. 15 The preparations were washed in three changes of Krebs solution for 10 minutes. The composition of the Krebs solution was (in mM) 120.9 NaCl, 5.9 KCl, 1.2 MgCl 2 , 1.2 NaH 2 PO 4 , 14.4 NaHCO 3 , 2.5 CaCl 2 , and 11.5 glucose.…”

Enteric Nervous System: Neuropathic Gastrointestinal Motility

“…Pharmacologic interest in 5-HT 4 receptors stems from specific investigative findings that enteric neurons express the mRNA transcript that encodes the 5-HT 4 receptor and that immunohistochemical methods show ENS neuronal surface expression of the receptor in mice and guinea pigs [84,85]. Exposure to 5-HT 4 receptor agonists enhances fast excitatory postsynaptic potentials at nicotinic synapses in ENS microcircuits of guinea pigs and mice [84,86,87].…”

Mast cell expression of the serotonin1Areceptor in guinea pig and human intestine

“…Preparations from the small intestine were obtained by microdissection for immunohistochemistry, Western blot analysis, and ELISA. Fresh preparations of healthy human small intestine were obtained from segments of jejunum discarded during Roux-en-Y gastric bypass surgeries, as described in previous reports from our laboratory (15,49). The Institutional Review Board of The Ohio State University Office of Research Risks Protection approved the human protocols (protocol 02H0208).…”

“…Whole-mount immunohistochemistry was done essentially as we described elsewhere (15,35). Therefore, the current presentation of methods summarizes and quotes from these papers.…”