Luminal 5-HT stimulates colonic bicarbonate secretion in rats (original) (raw)
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The American Journal of Surgery, 2005
Background: The 5-HT 3 receptor is a serotonin receptor believed to reside on enteric neurons. However, several studies belie an exclusive neural localization. Our hypothesis is that the 5-HT 3 receptor agonist, 2-methyl-5-HT (2Me5HT), induces chloride secretion despite neural blockade, which can be blocked by a 5-HT 3 receptor antagonist. Methods: Rat distal colon was stripped of its muscularis, mounted as mucosal sheets in Ussing chambers, and short-circuited. Adjacent sheets were pretreated with 1 mol/L of the neurotoxin, tetrodotoxin, and incubated with 2Me5HT (50 mol/L) alone or with a 5-HT 3 (0.3 mol/L ondansetron or 0.3 mol/L tropisetron) or a 5-HT 4 (0.3 mol/L GR11808) receptor antagonist. Short-circuit current (I SC) was measured continuously. Results: 2Me5HT caused an increase in I SC , which was significantly (P Ͻ.01, repeated measures analysis of variance) inhibited by ondansetron (n ϭ 8) and tropisetron (n ϭ 5) but not by GR11808. Conclusions: A 5-HT 3 receptor is present at the mucosal level that mediates chloride secretion by a nonneural pathway.
Is nitric oxide involved in 5-HT-induced fluid secretion in the gut?
Behavioural Brain Research, 1995
The present study was undertaken to test the hypothesis that 5-HT stimulates nitric oxide (NO) generating neurons, and that these neurons participate in the mediation of 5-HT-induced fluid secretion. 5-HT induced electrogenic CI secretion in guinea-pig distal colon. This response was abolished by tetrodotoxin but not by atropine. The maximum response to 5-HT (10-5 M) was inhibited by ~ 65% (P< 0.05, n = 6) by the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA, 10-4 M). The substrate of NO synthase, L-Arg (10-3 M) reversed the inhibition of 5-HT-induced secretions by L-NNA. 5-HT-induced diarrhea in fasted mice was reduced by atropine in vivo. NG-Nitro-L-Arg methyl ester (L-NAME, 1-32 mg/kg, i.p.) dose-dependently inhibited 5-HT (1 mg/kg)-induced diarrhea. The inhibitory effect of L-NAME was reversed by L-Arg, but not D-Arg (600 mg/kg, i.p., respectively). Taken together, these data suggest that 5-HT-induced fluid secretion in the gut is partly due to the activation of neurons that generate NO.
Constitutive nitric oxide release modulates neurally-evoked chloride secretion in guinea pig colon
Autonomic Neuroscience-basic & Clinical, 2000
The role of constitutive nitric oxide (NO) release in enteric neural pathways regulating ion transport was examined in guinea pig distal colon, in vitro and ex vivo. In in vitro studies, 43% of colonic preparations exhibited oscillations in baseline short-circuit current (I ), sc which were reduced by tetrodotoxin (TTX). The NO chelator, hemoglobin (Hb), and neuronal NO synthase inhibitor, 7-nitroindazole (7-NI), significantly increased the baseline I in these tissues, which was reduced by TTX. In tissues without oscillations in baseline I , sc sc
Mechanism of augmented duodenal HCO3- secretion after elevation of luminal CO2
AJP: Gastrointestinal and Liver Physiology, 2004
The proximal duodenum is exposed to extreme elevations of Pco2 because of the continuous mixture of secreted HCO3− with gastric acid. These elevations (up to 80 kPa) are likely to place the mucosal cells under severe acid stress. Furthermore, we hypothesized that, unlike most other cells, the principal source of CO2 for duodenal epithelial cells is from the lumen. We hence examined the effect of elevated luminal Pco2 on duodenal HCO3− secretion (DBS) in the rat. DBS was measured by the pH-stat method. For CO2 challenge, the duodenum was superfused with a high Pco2 solution. Intracellular pH (pHi) of duodenal epithelial cells was measured by ratio microfluorometry. CO2 challenge, but not isohydric solutions, strongly increased DBS to approximately two times basal for up to 1 h. Preperfusion of the membrane-permeant carbonic anhydrase inhibitor methazolamide, or continuous exposure with indomethacin, fully inhibited CO2-augmented DBS. Dimethyl amiloride (0.1 mM), an inhibitor of the b...
The FASEB Journal, 2006
Although duodenal mucosal bicarbonate secretion (DMBS) is currently accepted as an important defense mechanism against acid-induced duodenal injury, the mechanism and the regulation of DMBS are largely unknown. 5-HT may regulate DMBS, but little is known about its physiological relevance in DMBS and the underlying mechanism(s). Thus, the aims of the present study were to demonstrate the role of 5-HT in acid-stimulated DMBS and to further elucidate the precise mechanisms involved in this process. Luminal acid stimulation significantly increased 5-HT release from the duodenal mucosa (P<0.01). SB204070, a selective 5-HT 4 receptor antagonist, dose-dependently reduced luminal acid-stimulated HCO 3 ؊ secretion of mice in vivo. In Ussing chamber studies, 5-HT-induced I sc and DMBS were abolished by removal of extracellular Ca 2؉ , and significantly attenuated by pharmacological blockade of the Na ؉ /Ca 2؉ exchanger (NCX), intermediate Ca 2؉-activated K ؉ channels (IK Ca), or cystic fibrosis transmembrane conductance regulator (CFTR). 5-HT increased cytoplasmic free calcium ([Ca 2؉ ] cyt) in SCBN cells, a duodenal epithelial cell line, and knockdown of NCX1 proteins with a specific siRNA greatly decreased this 5-HT-mediated Ca 2؉ signaling. Taken together, our data suggest that 5-HT plays a physiological role in acid-stimulated DMBS via a Ca 2؉ signaling pathway, in which the plasma membrane NCX transporter as well as IK Ca and CFTR channels may be involved.-Smith, A. J., Chappell, A. E., Buret, A. G., Barrett, K. E., Dong, H. 5-Hydroxytryptamine (5-HT) contributes significantly to a reflex pathway by which the duodenal mucosa protects itself from gastric acid injury.
Disturbances of colonic ion secretion in inflammation: role of the enteric nervous system and cAMP
Pflügers Archiv, 2002
We used the trinitrobenzenesulphonic acid (TNBS) rat model of experimental colitis to study the alterations in electrogenic ion transport in the inflamed distal colon. The distal colon exhibited decreased basal transport and reduced short-circuit current responses to carbachol and isobutylmethylxanthine (IBMX). The concentration/response curve for IBMX was also shifted to the right. Ion substitution experiments indicated that electrogenic transport was attributable chiefly to Clsecretion. The mucosal layer of the inflamed distal colon (devoid of the submucosa) exhibited normal maximal responses to carbachol and IBMX, although the concentration/response curve for the latter was again shifted to the right. Tetrodotoxin markedly increased the response of the normal distal colon to both secretagogues and nullified the inhibition of the response to carbachol, but not that to IBMX, in the inflamed colon. The response of the mucosal preparation to 8-bromoadenosine 3′,5′-cyclic monophosphate was similar in the normal and inflamed intestine, while the G protein activator NaF had a greater effect in the latter. The expression of the cystic fibrosis transmembrane conductance regulator (CFTR), as assessed by Northern blotting, was unchanged. cAMP levels in isolated colonocytes were markedly reduced by inflammation. We conclude that colonic inflammation produces disturbances of the enteric nervous system resulting in defective mucosal cAMP production and inhibition of ionic secretion.
Gastroenterology, 2011
Background & Aims-An important component of enteric inhibitory neurotransmission is mediated by a purine neurotransmitter, such as adenosine 5'-triphosphate (ATP), binding to P2Y1 receptors and activating small conductance K + channels. In murine colon ß-nicotinamide adenine dinucleotide (ß-NAD) is released with ATP and mimics the pharmacology of inhibitory neurotransmission better than ATP. Here ß-NAD and ATP were compared as possible inhibitory neurotransmitters in human and monkey colons.