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1.
Int J Mol Sci ; 22(10)2021 May 14.
Article in English | MEDLINE | ID: mdl-34068986

ABSTRACT

A therapeutic potential of the TRPA1 channel agonist cinnamaldehyde for use in inflammatory bowel disease is emerging, but the mechanisms are unclear. Semi-quantitative qPCR of various parts of the porcine gastrointestinal tract showed that mRNA for TRPA1 was highest in the colonic mucosa. In Ussing chambers, 1 mmol·L-1 cinnamaldehyde induced increases in short circuit current (ΔIsc) and conductance (ΔGt) across the colon that were higher than those across the jejunum or after 1 mmol·L-1 thymol. Lidocaine, amiloride or bumetanide did not change the response. The application of 1 mmol·L-1 quinidine or the bilateral replacement of 120 Na+, 120 Cl- or 25 HCO3- reduced ΔGt, while the removal of Ca2+ enhanced ΔGt with ΔIsc numerically higher. ΔIsc decreased after 0.5 NPPB, 0.01 indometacin and the bilateral replacement of 120 Na+ or 25 HCO3-. The removal of 120 Cl- had no effect. Cinnamaldehyde also activates TRPV3, but comparative measurements involving patch clamp experiments on overexpressing cells demonstrated that much higher concentrations are required. We suggest that cinnamaldehyde stimulates the secretion of HCO3- via apical CFTR and basolateral Na+-HCO3- cotransport, preventing acidosis and damage to the epithelium and the colonic microbiome. Signaling may involve the opening of TRPA1, depolarization of the epithelium and a rise in PGE2 following a lower uptake of prostaglandins via OATP2A1.


Subject(s)
Acrolein/analogs & derivatives , Antineoplastic Agents, Phytogenic/pharmacology , Bicarbonates/metabolism , Epithelial Cells/metabolism , Gastrointestinal Tract/metabolism , TRPA1 Cation Channel/agonists , Acrolein/pharmacology , Animals , Epithelial Cells/drug effects , Gastrointestinal Tract/drug effects , Swine
2.
Acta Physiol (Oxf) ; 233(1): e13694, 2021 09.
Article in English | MEDLINE | ID: mdl-34031986

ABSTRACT

AIM: Absorption of ammonia from the gut has consequences that range from encephalitis in hepatic disease to global climate change induced by nitrogenous excretions from livestock. Since patch clamp data show that certain members of the transient receptor potential (TRP) family are permeable to NH4+ , participation in ammonium efflux was investigated. METHODS: Digesta, mucosa and muscular samples from stomach, duodenum, jejunum, ileum, caecum and colon of pigs were analysed via colourimetry, qPCR, Western blot, immunohistochemistry and Ussing chambers. RESULTS: qPCR data show high duodenal expression of TRPV6. TRPM6 was highest in jejunum and colon, with expression of TRPM7 ubiquitous. TRPM8 and TRPV1 were below detection. TRPV2 was highest in the jejunum but almost non-detectable in the colon. TRPV4 was ubiquitously expressed by mucosal and muscular layers. TRPV3 mRNA was only found in the mucosa of the caecum and colon, organs in which NH4+ was highest (>7 mmol·L-1 ). Immunohistochemically, an apical expression of TRPV3 and TRPV4 could be detected in all tissues, with effects of 2-APB and GSK106790A supporting functional expression. In symmetrical NaCl Ringer, removal of mucosal Ca2+ and Mg2+ increased colonic short circuit current (Isc ) and conductance (Gt ) by 0.18 ± 0.06 µeq·cm-2 ·h-1 and 4.70 ± 0.85 mS·cm-2 (P < .05, N/n = 4/17). Application of mucosal NH4 Cl led to dose-dependent and divalent-sensitive increases in Gt and Isc , with effects highest in the caecum and colon. CONCLUSION: We propose that TRP channels contribute to the intestinal transport of ammonium, with TRPV3 and TRPV4 promising candidate proteins. Pharmacological regulation may be possible.


Subject(s)
Ammonium Compounds , Transient Receptor Potential Channels , Animals , Biological Transport , Intestinal Absorption , Swine , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Transient Receptor Potential Channels/metabolism
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