Abstract
Alcohol disrupts the intestinal mucosal barrier by inducing metabolic and functional changes in epithelial cells. Recently, we showed that neuropeptide S (NPS) decreases duodenal motility and increases mucosal paracellular permeability, suggesting a role of NPS in the pathogenesis of disorders and dysfunctions in the small intestine. The aim of the present study was to investigate the effects of NPS on ethanol- and HCl-induced changes of duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. The effects on duodenal bicarbonate secretion, the blood-to-lumen clearance of 51Cr-EDTA, motility and transepithelial net fluid flux were investigated. Intravenous (i.v.) administration of NPS significantly reduced duodenal mucosal bicarbonate secretion and stimulated mucosal transepithelial fluid absorption, mechanisms dependent on nitrergic signaling. NPS dose-dependently reduced ethanol-induced increases in duodenal motility. NPS (83 pmol·kg-1·min-1, i.v.) reduced the bicarbonate and fluid secretory response to luminal ethanol, whereas a 10-fold higher dose stimulated fluid secretion but did not influence bicarbonate secretion. In NPS-treated animals, duodenal perfusion of acid (pH 3) induced greater bicarbonate secretory rates than in controls. Pre-treating animals with Nω-nitro-L-arginine methyl ester (L-NAME) inhibited the effect of NPS on bicarbonate secretion. In response to luminal acid, NPS-treated animals had significantly higher paracellular permeability compared to controls, an effect that was abolished by L-NAME. Our findings demonstrate that NPS reduces basal and ethanol-induced increases in duodenal motility. In addition, NPS increases luminal alkalinization and mucosal permeability in response to luminal acid via mechanisms that are dependent on nitric oxide signaling. The data support a role for NPS in neurohumoral regulation of duodenal mucosal barrier function and motility.
Highlights
Long-term and excessive consumption of alcohol is associated with the etiology of liver disease [1]
In control animals (n = 9) where the duodenal segment was perfused with isotonic saline only, duodenal bicarbonate secretion, motility index and net fluid flux were stable at an average of 12.6±0.97 μmolÁcm-1Áh-1 (Fig 1A), 407±27 AUC/10 min and 0.58±0.15 mlÁg-1Áh-1 (Fig 1C), respectively, while duodenal mucosal paracellular permeability decreased modestly in a linear fashion from the start to the end of experiment
It was shown that hydrochloric acid at a pH of 3 did not change the 15% ethanol-induced increases in duodenal bicarbonate secretion and mucosal paracellular permeability
Summary
Long-term and excessive consumption of alcohol is associated with the etiology of liver disease [1]. Moderate intake of alcohol has been shown to be beneficial by lowering the risk. Ethanol- and acid-changes in duodenal barrier function of coronary heart disease [2, 3]. Alcohol is absorbed by the epithelium in the foregut, mainly in the duodenum and to some minor extent in the stomach [4, 5]. Previous experiments from our laboratory showed that perfusing the duodenal lumen with 15% ethanol in saline induces potent increases in mucosal paracellular permeability [6]. The neuroendocrine hormone melatonin was shown to reduce the ethanol-induced increases in duodenal paracellular permeability partly via an enteric neural pathway in a dosedependent manner. Melatonin was shown to inhibit increases in duodenal motor activity in response to luminal ethanol [6, 7]. It is plausible that the endogenous gastrointestinal neuroendocrine system may influence the magnitude of ethanol-induced changes to the regulation of tight junctional protein displacement and motility [6, 7]
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