The mechanisms of sodium absorption in the human small intestine

The present studies were designed to characterize sodium transport in the jejunum and ileum of humans with respect to the effects of water flow, sodium concentration, addition of glucose and galactose, and variations in aniomic composition of luminal fluid. In the ileum, sodium absorption occurred against very steep electrochemical gradients (110 mEq/liter, 5-15 mv), was unaffected by the rate or direction of water flow, and was not stimulated by addition of glucose, galactose, or bicarbonate. These findings led to the conclusion that there is an efficiently active sodium transport across a membrane that is relatively impermeable to sodium. In contrast, jejunal sodium (chloride) absorption can take place against only the modest concentration gradient of 13 mEq/liter, was dramatically influenced by water movement, and was stimulated by addition of glucose, galactose, and bicarbonate. The stimulatory effect of glucose and galactose was evident even when net water movement was inhibited to zero by mannitol. These observations led to the conclusion that a small fraction of jejunal sodium absorption was mediated by active transport coupled either to active absorption of bicarbonate or active secretion of hydrogen ions. The major part of sodium absorption, i.e. sodium chloride absorption, appeared to be mediated by a process of bulk flow of solution along osmotic pressure gradients. The stimulatory effect of glucose and galactose, even at zero water flow, was explained by a model in which the active transport of monosaccharide generates a local osmotic force for the absorption of solution (NaCl and water) from the jejunal lumen, which, in the presence of mannitol, is counterbalanced by a reverse flow of pure solvent (H(2)O) through a parallel set of channels which are impermeable to sodium. Support for the model was obtained by the demonstration that glucose and bicarbonate stimulated the absorption of the nonactively transported solute urea even when net water flow was maintained at zero by addition of mannitol to luminal contents.     

The site-specific transport and metabolism of tacrolimus in rat small intestine

The objective of this study was to evaluate the absorption of tacrolimus by means of simultaneous perfusion of intestinal lumen and blood vessels in rats. In our previous report, the permeability of tacrolimus was found to be higher in the jejunum than in the ileum or colon, suggesting the site-dependent absorption after oral administration. However, in this article, simultaneous perfusion technique revealed that the extent of absorption into blood vessels was similar in the jejunum and the ileum regardless of the site difference in permeability as the absorption rate. In addition to the multidrug resistance-associated protein-mediated efflux, cytochrome P450 (P450)-mediated metabolism could be a possible mechanism to explain the inconsistencies in the site dependence of tacrolimus absorption. Two enzyme inhibitors, ketoconazole and midazolam, were coperfused in rat intestinal lumen with tacrolimus to specify the effect of P-gp and P450. In the jejunum, both inhibitors significantly enhanced the absorbed amount of tacrolimus, whereas the permeability was not affected. It was suggested that both inhibitors mainly suppress P450-mediated metabolism in the upper region of the intestine. In contrast, in the ileum, ketoconazole significantly enhanced both the absorbed amount and the permeability of tacrolimus. However, midazolam failed to enhance the absorption of tacrolimus, indicating the dominant role of P-glycoprotein (P-gp)-mediated efflux in the lower region. From these findings, it is concluded that the site-dependent differences in P-gp and/or P450 activity could be the prime cause of large intra- and interindividual variability in the oral absorption of tacrolimus.     

Glucose and glutamine metabolism in the small intestine of septic rats

The intestinal metabolism of glucose and glutamine was studied in rats made septic by cecal ligation and puncture technique. Sepsis resulted in negative nitrogen balance and produced increases in the concentrations of blood pyruvate, lactate, alanine, and glutamine, and decreases in those of 3-hydroxybutyrate and acetoacetate. Both plasma insulin and glucagon concentrations were increased by 2.2- and 3.2-fold in septic rats, respectively. Portal-drained visceral blood flow increased in septic rats, and was accompanied by a decrease in the rates of utilization of glutamine and production of lactate, glutamate, and ammonia compared with those rates in sham-operated animals. Enterocytes isolated from septic rats showed decreased rates of glucose and glutamine utilization compared with cells isolated from corresponding controls. The maximal activities of hexokinase, 6-phosphofructokinase, pyruvate kinase, and glutaminase were decreased in intestinal mucosal scrapings of septic rats. It is concluded that a moderate form of sepsis decreases the rates of glucose and glutamine utilization (both in vivo and in vitro) by the epithelial cells of the small intestine. This may be caused by changes in the maximal activities of key enzymes in the pathways of glucose and glutamine metabolism in these cells as a metabolic adaptation to spare glucose and glutamine for use by other tissues.     

小肠部分切除大鼠术后一氧化氮代谢途径干预对葡萄糖代谢的影响

目的：观察小肠部分切除大鼠术后一氧化氮代谢途径干预对大鼠术后葡萄糖代谢的影响，寻找解决术后胰岛素抵抗的方法。方法：实验于2005—01／2006—08在解放军第四军医大学第二附属医院中心实验室完成。实验分组：96只大鼠随机数字表法分为4组，正常对照组，L-硝基-精氨酸甲酯处理组，L-精氨酸处理组，L-精氨酸＋L-硝基-精氨酸甲酯处理组，每组24只。实验干预：建立大鼠小肠部分切除模型，各干预组分别尾静脉注射1mg／kg L-硝基-精氨酸甲酯、100mg／kg L-精氨酸处理、0．5mg／kg L-硝基-精氨酸甲酯＋50mg／kg L-精氨酸处理进行一氧化氮代谢途径干预。正常对照组只注射1mL生理盐水。实验评估：①给药后2，8，12，24，48h取血，测定血清中一氧化氮含量及血糖检测。②给药后24h，48h，1周后采用胰岛素敏感性实验计算每公斤代谢体质量每分钟代谢葡萄糖的量。结果：96只大鼠均进入结果分析。①血清一氧化氮含量：L-硝基-精氨酸甲酯处理组各时间点血清一氧化氮含量低于正常对照组（P〈0、05），而L-精氨酸处理组各时间点血清一氧化氮含量高于正常对照组（P〈0．05）；L-精氨酸＋L-硝基-精氨酸甲酯处理组与正常对照组比较差异无显著性（P〉0．1）。②空腹血糖：给药后8，12，24，48h L-硝基-精氨酸甲酯处理组高于正常对照组（P〈0．05）。给药后8，12，24，48h L-精氨酸处理组低于正常对照组（P〈0．05）；L-精氨酸＋L-硝基-精氨酸甲酯处理组与正常对照组比较差异无显著性（P〉0．1）。③稳态情况下每千克代谢体质量每分钟代谢葡萄糖的量：L-硝基-精氨酸甲酯处理组显著低于正常对照组（P〈0．05），而L-精氨酸处理组则显著高于正常对照组（P〈0．05）；L-精氨酸＋L-硝基-精氨酸甲酯处理组与正常对照组比较差异无显著性（P〉0．1）。结论：小肠部分切除大鼠术后一氧化氮代谢途径在葡萄糖转运和胰岛素活性方面可能起着重要作用，提示其可能是解决术后胰岛素抵抗的一种方法。     

Absorption of L-methionine from the human small intestine

Absorption of L-methionine was measured in all parts of the human small intestine using transintestinal intubation and perfusion. In four normal subjects, adsorption was higher in the proximal than in the distal intestine. In two patients with nontropical sprue in relapse, there was a proximal zone of low absorption with higher absorption distally. In all parts of the small intestine, absorption showed rate-limiting kinetics as methionine concentration was increased. In normal subjects, the proximal K(m) (Michaelis constant) was more than 3 times higher than the distal, which suggests a difference in transport mechanisms between the two segments.     

Effects of dexamethasone on glutamine metabolism in the isolated vascularly perfused rat small intestine

Post-stress metabolism is associated with a large glutamine (Gln) efflux from muscle and an increased Gln utilization by the small intestine. Both appear to be modulated by corticosteroids. The present investigation was performed to better characterize the mechanism of corticoid action on Gln metabolism in an isolated preparation of vascularly perfused rat small intestine. In all perfusions, a synthetic perfusate free from blood components was used with only 0.6 mM Gln and 10 mM glucose as substrates. Irrespective of dexamethasone concentrations in the vascular perfusate (none, 0.25 mg l⁻¹, or 2.5 mg l⁻¹), isolated intestines from normal rats exhibited unchanged extraction rates of Gln (−85±8, −89±10, and −87±16 nmol min⁻¹ g⁻¹) and unchanged production rates of alanine (43±9, 40±7, and 51±5 nmol min⁻¹ g⁻¹) and ammonia (49±15, 45±13, and 54±13 nmol min⁻¹ g⁻¹). Similarly, when intestines were vascularly perfused 2 or 9 days after dexamethasone injection (0.45 mg kg⁻¹ BW), net Gln uptake also remained unchanged (−88±16 and −84±11 nmol min⁻¹ g⁻¹). There was, however, a shift in nitrogenous products of Gln metabolism from ammonia (−31% and −38%) to alanine (+16% and +64%). Thus, the failure of dexamethasone to increase Gln uptake in the isolated rat intestine may indicate that rather than acting directly on the mucosa, dexamethasone could regulate intestinal Gln consumption in vivo by indirect mechanisms possibly involving extramucosal tissues. Dexamethasone pretreatment may modulate the pattern of nitrogenous products in portal venous blood presented to the liver and thus support enhanced nitrogen loss through ureagenesis by metabolic cooperation between gut and liver.     

Absorption of inorganic phosphate in the human small intestine.

1. Intestinal phosphate absorption in human subjects was studied by the technique of triple lumen intestinal perfusion in vivo. 2. Ileal phosphate absorption increased as the intraluminal phosphate concentration was increased. 3. Ileal rates of phosphate absorption were lower at any given intraluminal phosphate concentration than previously described jejunal rates. Acidification of the ileal lumen did not increase phosphate absorption. 4. Phosphate absorption was shown in the jejunum to be dependent on the intraluminal sodium concentration. 5. Phosphate absorption in the human small intestine consists of at least two components, one directly proportional to water movement and the second apparently independent of water movement.