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Query: UMLS:C0022104 (
irritable bowel syndrome
)
8,033
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Methylglyoxal (MG), a highly reactive dicarbonyl substance, is known as an endogenous carbonyl stress-inducing substance related to various disease states.
Irritable bowel syndrome
(
IBS
) is one of the most frequently encountered gastrointestinal disorders and MG is considered to be its causal substance. An increased serum 5-hydroxytryptamine (5-HT) level is related to
IBS
symptoms and the majority of 5-HT originates from enterochromaffin (EC) cells in the intestine. Here we examine the mechanisms of MG-induced 5-HT secretion using RIN-14B cells derived from a rat pancreatic islet tumor since these cells are used as a model for EC cells. MG increased the intracellular Ca(2+) concentration ([Ca(2+)]i) and 5-HT secretion, both of which were inhibited by the removal of extracellular Ca(2+) and specific transient receptor potential
ankyrin 1
(TRPA1) antagonists. MG elicited an inward current under voltage-clamped conditions. Prior application of MG evoked reciprocal suppression of subsequent [Ca(2+)]i responses to allylisothiocyanate, a TRPA1 agonist, and vice versa. Glyoxal, an analog of MG, also evoked [Ca(2+)]i and secretory responses but its potency was much lower than that of MG. The present results suggest that MG promotes 5-HT secretion through the activation of TRPA1 in RIN-14B cells. These results may indicate that TRPA1 is a promising target for the treatment of
IBS
and that the RIN-14B cell line is a useful model for investigation of
IBS
.
...
PMID:Carbonyl stress-induced 5-hydroxytriptamine secretion from RIN-14B, rat pancreatic islet tumor cells, via the activation of transient receptor potential ankyrin 1. 2742 12
Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with
irritable bowel syndrome
(
IBS
). Sensitization of TRP
ankyrin 1
(TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with
IBS
. Rectal biopsies were collected from patients with
IBS
and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca
2+
imaging. In addition, the effect of supernatants of rectal biopsies on patients with
IBS
and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H
1
R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with
IBS
compared with HS. In HS, pretreatment with histamine significantly increased the Ca
2+
responses to cinnamaldehyde and GSK1016790A, an effect prevented by H
1
R antagonism.
IBS
supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H
1
R antagonism. We demonstrate that the mucosal microenvironment in
IBS
contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H
1
R activation, most likely contributing to increased visceral pain perception in
IBS
. These data further underscore H
1
R antagonism as potential treatment for
IBS
. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP)
ankyrin 1
and TRP vanilloid 4 sensitization in
irritable bowel syndrome
(
IBS
) via histamine 1 receptor (H
1
R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of
IBS
and provide novel mechanistic insights into the therapeutic potential of H
1
R antagonism in
IBS
.
...
PMID:Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome. 3062 70
