Enterotrophic effects of glucagon-like peptide 2 are enhanced by neurotensin

Combination therapy with enterotrophic agents may be useful in patients with the short bowel syndrome. The gut hormones neurotensin (NT) and glucagon-hke peptide 2 (GLP-2) are potent enterotrophic fattors when administered alone; however, their combined effects are not known. Using a GLP-2-producing tumor (STC-1), we determined whether administration of NT enhances the effect of GLP-2 on intestinal growth. Athymic mice were injected with STC-1 cells (6 × 10⁶) subcutaneously. Twenty-three days after STC-1 implantation, mice received either NT (300 μg/kg or 600 μg/kg) or saline solution (control) subcutaneously three times a day for 6 days. Two groups of tumor-free mice received either saline or NT for 6 days. At sacrifice, jejunum and ileum were collected, weighed, and analyzed for DNA and protein content. In the jejunum, NT combined with GLP-2 (from STC-1) increased weight, protein content (markers of mucosal hypertrophy), and DNA content (a marker of mucosal hyperplasia), compared to either NT or GLP-2 alone. In the ileum, the combination of NT and GLP-2 significantly increased weight and/or protein content compared to NT or GLP-2 alone. Administration of NT enhances the enterotrophic effects of GLP-2, augmenting hypertrophy of the entire small bowel and hyperplasia of the jejunum. The combination of NT and GLP-2 may be useful to enhance intestinal growth in patients with the short bowel syndrome. Supported in part by National Institutes of Health grants PO1 DK356O8, ROI DK48345, ROI AG10885, and T32 DK07633. Presented in part at the Surgical Forum of the American College of Surgeons, Chicago, Ill., October 12–17, 1997; and at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

Differential effects of gut hormones on pancreatic and intestinal growth during administration of an elemental diet.

Liquid elemental diets (ED) will, in time, cause atrophy of the gut. Pentagastrin (PG), neurotensin (NT), and bombesin (BBS) are peptides that have trophic effects on the gut of normal rats. This study examined the effect of these three agents on gut atrophy produced by ED. Four groups of rats were given an ED and injected with either saline (control), PG (250 micrograms/kg), NT (300 micrograms/kg), or BBS (10 micrograms/kg) subcutaneously every 8 hours for 5 or 10 days. A fifth group was fed rat chow ad libidum. The rats were killed on day 6 or 11; the pancreas and segments of small intestine were removed. Atrophy of ileal mucosa was apparent on days 6 and 11, and atrophy of jejunal mucosa was manifest by day 11. Bombesin prevented jejunal mucosal atrophy and significantly increased ileal mucosal growth (compared with control). Neurotensin prevented the jejunal, but not the ileal, mucosal atrophy produced by ED. Pentagastrin had no effect on gut mucosa. Bombesin and PG, but not NT, stimulated pancreatic growth. Neurotensin stimulates pancreaticobiliary secretions (PBS), which are known to stimulate gut growth. Jejunoileal bypass was performed to determine whether trophic effects of NT on gut mucosa were mediated through stimulation of PBS. After 1 week treatment, animals were killed and segments of intestine removed. As expected NT was trophic for gut mucosa in continuity with the luminal stream; furthermore NT produced significant stimulation of growth of gut mucosa in the bypassed segment. We conclude that both BBS and NT are trophic for intestinal mucosa of rats given ED; both agents have a more pronounced effect on jejunum. The trophic effect of NT is mediated, in part, by a mechanism unrelated to stimulation of PBS. Bombesin and NT may have important regulatory functions in the adaptive growth of small bowel mucosa and in the maintenance of gut mucosal integrity.     

Bombesin stimulates mucosal growth in jejunal and ileal Thiry-Vella fistulas.

OBJECTIVE: The authors determined whether the trophic effects of bombesin (BBS) on the small bowel mucosa are mediated by either nonluminal factors or endogenous luminal secretion. SUMMARY BACKGROUND DATA: The gut hormone bombesin stimulates growth of small bowel mucosa. The mechanisms responsible for this trophic effect are not known. METHODS: Rats underwent construction of a Thiry-Vella fistula (TVF) of either the jejunum or ileum. On postoperative day 10, the two groups were subdivided to receive either saline (control) or bombesin (10 micrograms/kg, subcutaneously, three times a day). After 14 days, rats were killed and the TVF was removed. The mucosa was scraped and weighed, and DNA and protein content was determined. RESULTS: Bombesin significantly increased mucosal weight and DNA and protein content of both the jejunal and ileal TVF compared with the control rats. CONCLUSIONS: Bombesin-mediated stimulation of small bowel mucosal growth is mediated by factors that are independent of luminal contents and pancreaticobiliary secretion. Bombesin may prove to be an important enterotrophic factor for gut mucosal proliferation.     

Effect of gut transposition on the expression of the endocrine gene neurotensin

Expression of the gene encoding neurotensin (NT/N) is developmentally regulated in the adult small bowel with maximal expression noted in the distal ileum; the mechanisms responsible for this strict spatial-specific expression pattern are not known. The purpose of this study was to determine whether NT/N expression is altered by ileojejunal transposition. Rats underwent either sham operation or ileojejunal transposition and were killed 2 months after operation. The transposed (either jejunum or ileum) and sham-operated segments of gut were removed, a portion was processed for histologic examination, and the remainder was extracted for total RNA and analyzed by ribonuclease protection using a rat NT/N probe. For comparison, expression of another gut endocrine gene, peptide YY, and an enterocyte-specific gene, sucrase-isomaltase (SI), was also determined. Expression of the gut endocrine genes, NT/N and peptide YY, were minimally affected by transposition of either the jejunum or ileum. In contrast, SI expression was markedly altered in both the transposed jejunum and ileum compared with corresponding sham gut segments. Expression of the NT/N gene is minimally altered after jejunoileal transposition despite marked adaptive and morphologic changes in the transposed segments. These findings provide further support that the strict pattern of NT/N expression is “imprinted” in the gut and maintained regardless of location along the cephalocaudal gut axis. Supported by grants AG10885, DK48498, and DK35608 from the National Institutes of Health and the James E. Thompson Memorial Foundation. Presented at the Thirty-Eighth Annual Meeting of The Society for the Surgery of the Alimentary Tract, Washington, D.C., May 11–14, 1997. An abstract of this work was published in Gastroenterology 112:A1484, 1997.     

胰高血糖素样肽-2对短肠大鼠残留小肠代偿的影响

目的研究胰高血糖素样肽-2(GLP-2)对短肠大鼠残留小肠形态及功能代偿的影响。方法将20只切除小肠75%的大鼠随机分成对照组和GLP-2组,术后1-5 d内自由进食。GLP-2组每日2次腹腔注射GLP-2(250μg·kg~(-1)·d~(-1))；对照组每日2次腹部皮下注射生理盐水0．5 ml；另设1组正常进食大鼠作空白对照。术后第6天行残留小肠黏膜形态学检测、细胞增殖核心抗原(PCNA)测定,钠葡萄糖共同转运体(SGLT1)和二肽转运体(PEPT1)的mRNA表达检测以及在体小肠循环灌流实验测定大鼠回肠的单位长度及单位重量的葡萄糖吸收率。结果GLP-2组残留小肠黏膜形态学指标、PCNA指数显著高于对照组；而小肠黏膜细胞凋亡显著低于对照组；残留回肠SGLT1和PEPT1的mRNA表达显著高于对照组；均P＜0．05。但两组灌洗段回肠每g湿重葡萄糖吸收率差异无统计学意义(P＞0．05)。结论GLP-2能刺激小肠黏膜上皮增生、抑制凋亡,促进短肠大鼠残留小肠黏膜的形态及功能代偿。     

Neurotensin augments intestinal regeneration after small bowel resection in rats.

Massive small bowel resection (SBR) is characterized by increased proliferation of residual gut mucosa and pancreas. Neurotensin (NT), a gut tridecapeptide, stimulates growth of normal gut mucosa and pancreas. This study examined whether NT affected growth of the small intestine and the pancreas after either distal or proximal SBR. Male Fischer 344 rats were divided into four groups. Group 1 underwent ileal transection with reanastomosis (SHAM) and group 2 underwent 70% distal SBR. Group 3 underwent SHAM operation (jejunal transection), and group 4 underwent 70% proximal SBR. After operation, each group was further subdivided to receive either saline (control) or NT (300 micrograms/kg) subcutaneously in gelatin every 8 hours for 7 days. At death, the pancreas and proximal jejunum (from groups 1 and 2) or distal ileum (from groups 3 and 4) were removed, weighed, and analyzed for DNA, RNA, and protein content. Both proximal and distal SBR significantly increased mucosal growth in the remnant intestine; a more pronounced effect was noted with proximal SBR. Administration of NT significantly augmented the adaptive changes in both groups of rats by mechanisms involving increases in both cell size (hypertrophy) and cell number (hyperplasia). Pancreatic growth was stimulated by distal (but not proximal) SBR; NT did not augment this response. The authors conclude that NT augments intestinal growth after SBR by mechanisms involving an increase in overall mucosal cellularity. Administration of NT may be therapeutically useful to enhance mucosal regeneration during the early period of adaptive hyperplasia after SBR.     

Combined effects of glutamine and epidermal growth factor on the rat intestine

Glutamine (GLN) is an important fuel and epidermal growth factor (EGF) is a potent mitogen for intestinal mucosa cells. GLN-enriched parenteral nutrition was administered to male Wistar rats, and subcutaneous injections of EGF were given for 3, 6, and 7 days. Control animals were fed a non-GLN-containing solution. Other groups of animals received GLN or EGF alone. Mucosal samples were obtained from the jejunum, ileum, and colon for measurement of weight, DNA, protein, and mucosal thickness. Disaccharidase activity was measured in the jejunum. After 3 days, only animals that received both GLN and EGF had a significant increase in small-bowel mucosal protein and thickness relative to controls. A similar pattern was observed in the colon, where animals that received both agents had a greater mucosal thickness, DNA, and protein content than controls. At 7 days, animals that received EGF or GLN had greater nitrogen retention. In addition, animals that were treated with EGF had elevated sucrase and maltase activity compared with GLN-fed animals at this time. Animals treated with GLN and EGF tended to have increased sucrase activity relative to controls. GLN feeding was associated with increased mucosal DNA and protein contents throughout the intestine for the combined series. EGF increased mucosal DNA and protein in the small intestine but not in the colon. The effect of EGF on the protein content of the small-bowel mucosa was dose dependent. The effects of GLN and EGF on the small bowel and colonic mucosa were additive. These studies suggest that specific nutrients and hormones may be used in combination to decrease the mucosal atrophy that commonly occurs after gut disuse or disease.     

Gastrointestinal adaptation following small bowel bypass for obesity.

Small intestinal morphologic and biochemical changes were studied following jejuno-ileal bypass for obesity after body weight stabilization had occurred. Four patients underwent biopsy of in-continuity and bypassed jejunal and ileal segments of the small intestine 11 to 22 months after the bypass operation. Microscopically, marked mucosal villus hypertrophy of the in-continuity bowel was observed, especially in the ileum. Bypassed jejunal mucosa underwent atrophy compared with pre-bypass jejunum, whereas bypassed ileum appeared similar microscopically to pre-bypass ileum. The specific activities of mucosal disaccharidase enzymes (maltase, sucrase, lactase and trehalase) in units per mg protein remained similar to pre-bypass levels in segments of the in-continuity jejunum and the bypassed jejunum and ileum. On the other hand, elevated mucosal disaccharidase levels were measured in biopsy specimens of the in-continuity ileum. Total enzyme activity per unit length of intestine, however, was estimated to be elevated in both in-continuity jejunum and ileum secondary to mucosal villus hypertrophy. These data indicate that following small bowel bypass: (1) the in-continuity ileum undergoes greater biochemical and morphologic adaptation than the jejunum; and (2) intraluminal nutrients and chyme appear to be essential to maximal intestinal adaptation.     

Systemic GLP-2 levels do not limit adaptation after distal intestinal resection

BACKGROUND/PURPOSE: Glucagonlike peptide 2 (GLP-2) is trophic for the small bowel; it is produced by L cells in the distal intestine in response to luminal nutrients. This study tests the hypothesis that distal small bowel and cecal resection would decrease GLP-2 levels and reduce adaptation. METHODS: Male Sprague-Dawley rats (200 to 300 g) underwent either ileal transection (controls) or resection of the ileum and cecum, leaving 10 or 20 cm jejunal remnant anastomosed to the ascending colon. Animals were followed up for up to 21 days. Endpoints were daily weights, intestinal histology, in vivo absorption of 3-0 methylglucose (a measurement of active nutrient absorptive capacity), and serum GLP-2 levels. RESULTS: The control group had a maximum 6% weight loss around day 2, and then recovered with a steady weight gain. The 10-cm jejunal remnant group lost weight continuously and never recovered postsurgery. The 20-cm jejunal remnant group of animals had a maximum of 12% weight loss by day 4 and then slowly gained weight. The average villus height increased significantly (P <.01) in the 10-cm and 20-cm jejunal remnant groups compared with controls. Absorption of 3-0 methylglucose was significantly decreased (P <.01) in both resected groups. Serum GLP-2 levels were increased significantly (P <.05) when compared with controls in both resection groups. CONCLUSIONS: Increased serum GLP-2 levels were found in the ileocecal resection rat model, and these levels correlated with morphologic adaptation. However, this morphologic adaptation was not sufficient to restore nutrient absorption as shown by weight changes and 3-0 methylglucose absorption. Thus, the original hypothesis of this study is incorrect: systemic GLP-2 levels do not limit adaptation following distal ileocecal resection.     

The role of apoptosis during intestinal adaptation after small bowel resection

BACKGROUND/PURPOSE: Adaptation after small bowel resection (SBR) is characterised by a new set point in the balance of enterocyte proliferation and apoptosis. Apoptosis is gene directed. The authors hypothesised that the adaptive response is influenced positively by antiapoptotic gene products (eg, bcl-2 gene-produced protein). The authors tested this hypothesis by studying the effect of bcl-2 overexpression on intestinal adaptation after SBR. METHODS: Male bcl-2 transgenic mice, overexpressing bcl-2 in the small intestinal epithelium, and wild type control mice underwent either a 75% mid-SBR, or a sham operation. The 4 experimental groups consisted of resection wild type (n = 8), transection wild type (n = 6), resection bcl-2 transgenic (n = 8), and transection bcl-2 transgenic (n = 8). Seven days postoperatively small bowel was harvested; total weight, mucosal weight, and mucosal protein, DNA, and RNA content in jejunal and ileal tissue were determined to quantitate the hyperplastic response. RESULTS: Compared with sham-operated animals, SBR resulted in increased total jejunal weight; mucosal weight; and mucosal protein, DNA, and RNA content. Furthermore, in the SBR groups, the jejunal mucosal weight and mucosal protein and DNA content were significantly higher in the bcl-2 transgenic mice compared with the wild-type mice. No differences were observed between any of these parameters in the transection wild-type and transgenic mice. In the ileum, similar changes were observed. The differences between resected and transected wild-type mice were less pronounced, and only total ileal weight and mucosal protein content reached statistical significance. In the transgenic animals, all ileal variables, with the exception of mucosal RNA content, were significantly higher in the SBR group than in the transected group. SBR in the transgenic mice resulted in higher ileal mucosal weight and mucosal protein, DNA, and RNA content compared with the wild-type mice. CONCLUSIONS: The results show that the murine SBR model is a true representation of the process of adaptation after SBR. Furthermore, major components of the adaptive response, both in the jejunum and in the ileum, are significantly more pronounced in the bcl-2 transgenic mice than in the wild-type control animals. Thus, it can be concluded that intestinal hyperplasia after SBR is significantly enhanced by overexpression of the anti-apoptotic bcl-2 gene product. This finding should prompt further research on the effects of antiapoptotic interventions on adaptation after SBR.     

Beneficial effects of oral insulin on intestinal recovery following ischemia-reperfusion injury in rat

BACKGROUND: It has been reported that oral insulin has a trophic effect on intestinal mucosa, but the precise mechanism of its action is still unclear. The purpose of the present study was to investigate the effect of oral insulin on ischemia-reperfusion (IR) intestinal mucosal injury in rat. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent laparotomy (Sham) or IR-intestinal damage by clamping both the superior mesenteric artery and the portal vein for 30 min followed by 24 h reperfusion. IR-INS rats were treated with oral insulin given in drinking water (1U/ml) 48 h before and after IR. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined 24 h after IR. Park's score was used for the quantitative assessment of histological change. A non-parametric Kruskal-Wallis ANOVA test was used for statistical analysis with P less than 0.05 considered statistically significant. RESULTS: IR-injury resulted in a significant decrease in bowel weight in jejunum, mucosal weight in jejunum and ileum, villus height in jejunum and ileum, cell proliferation index in jejunum, and ileum compared to sham animals. IR-INS animals demonstrated greater duodenal and jejunal bowel weight, duodenal, jejunal and ileal mucosal weight, jejunal mucosal DNA, jejunal and ileal mucosal protein, jejunal and ileal villus height and crypt depth, jejunal and ileal proliferation index compared to IR-animals. Oral insulin administration induced also a significant decrease in apoptotic index in ileum (1.2 +/- 0.4 versus 2.8 +/- 0.7 TUNEL positive cells/10 villi, P < 0.05) compared to IR-untreated animals. CONCLUSIONS: Oral insulin improves intestinal recovery after IR- injury in rat.     

不同生长因子对短肠大鼠残留小肠葡萄糖吸收的影响

目的 比较生长激素(GH)和胰高血糖素样肽-2(GLP-2)对短肠大鼠残留小肠葡萄糖吸收的影响.方法 75%小肠切除大鼠随机分成短肠(SB)组、GH组和CLP-2组.另设1组正常进食大鼠作SB组的对照组.术后1～5 d内自由进食,术后6 d进行在体小肠循环灌流实验测定大鼠回肠单位长度及单位重量的葡萄糖吸收结.结果 GH组和GLP-2组的灌洗段同肠湿重/长度比值及每厘米45 min葡萄糖吸收量均分别显著高于SB组(P<0.05).灌洗段回肠每克湿重葡萄糖吸收率正常组和GH组均显著高于SB组,但SB组和GLP-2组差异无统计学意义(P>0.05).结论 GH和GLP-2都能促进SBS大鼠残留小肠单位长度的葡萄糖吸收,并且两者的促进效能相似.     

短肠综合征合并高位肠瘘患者施行亲属活体小肠移植一例

目的总结短肠综合征合并高位肠瘘患者施行亲属活体小肠移植的经验和体会。方法为1例因肠系膜上动脉栓塞而切除空肠、大部分回肠及右半结肠的患者施行亲属活体小肠移植,供者为患者之子,移植回肠长度为150 cm,供肠热缺血时间1 min,冷缺血时间65 min。受者切除肠瘘,供肠动、静脉分别与受者的腹主动脉和下腔静脉行端侧吻合,供肠的近端与受者的空肠残端行端端吻合,远端侧壁与结肠残端行侧端吻合,移植小肠末端造口,作为观查窗。术后使用他克莫司、霉酚酸酯和甲泼尼龙预防排斥反应,并给予抗感染、抗凝以及胃肠外为主、肠内营养为辅的支持治疗。结果术后移植小肠功能接近正常,能胜任一般的体力劳动。术后110 d,患者因情绪变化突发心脏意外,抢救无效死亡。结论合并肠瘘的短肠综合征并非小肠移植禁忌证,术前充分准备和术后细致观察及管理是成功的关键。     

Evaluation of the longitudinal musculature of segments of the distal colon interposed following extended jejunum-ileum resection

Several morbid conditions may necessitate extensive intestinal resection, leading to short-bowel syndrome. When clinical treatment becomes inefficient, a surgical approach is necessary. Distal colon interposition is one of the viable techniques. The interposition of colon segments between remnants of the small bowel improved lifestyle, increased transit time, and diminished diarrhea. The aim of this study is to observe the longitudinal muscular contractions after distal colon interposition. Sixteen male Wistar rats (EPM-1) were submitted to an 80% small bowel resection associated with a partial colectomy of the distal colon immediately after the bifurcation of the middle colic artery followed by a 3-cm isoperistaltic distal colon interposition. After 70 days, the animals were submitted to euthanasia and segments of the jejunum, ileum, remnant colon, and interposed colon were prepared for pharmacological tests. The isometric contractions were measured by a polygraph. After 30 minutes, the dose/effect curves were obtained for both metacholine and barium chloride stimulation through the extraluminal surface (serosa). After this period, we observed a significant increase in the length, diameter, and thickness of the intestinal wall. Regarding the sensibility (pD(2)), no difference was found (interposed colon = 7.21 +/- 0.2; remnant colon = 7.65 +/- 0.1; remnant jejunum 7.46 +/- 0.1; and remnant ileum 7.57 +/- 0.1), even though the animals were submitted to different procedures. In relation to the maximal effect (E(max)), the longitudinal muscle contraction responses (interposed colon = 11.79 +/- 0.1; remnant jejunum = 15.42 +/- 0.2; and remnant ileum = 11.48 +/- 0.2) were lower than those of the remnant colon (E(max) = 22.42 +/- 0.1). This means that there was a possible adaptation of colonic segments to their new location.     

Elemental diet-induced bacterial translocation can be hormonally modulated.

BACKGROUND: The authors have previously documented that feeding mice an elemental diet resulted in bacterial translocation (BT) that could be prevented by the provision of dietary fiber. To test whether the protective effect of fiber was related to the stimulation of trophic gut hormones, the effects of sandostatin and bombesin were tested. METHODS: Mice fed either chow or the elemental diet were stratified into several groups and the ability of bombesin (10 micrograms/kg, tid) or sandostatin (100 micrograms/kg bid) to modulate BT was examined. After 14 days, mice were sacrificed and BT, cecal bacterial population levels, mucosal protein, and small bowel weight was measured. Segments of the ileum and jejunum were examined histologically. RESULTS: Incidence of elemental diet-induced BT (75%) was reduced by fiber (9%) or the administration of bombesin (13%) (p < 0.01). Although sandostatin did not promote BT in chow-fed mice, it reversed the protective effect of fiber on BT (75%) (p < 0.01). CONCLUSION: Elemental diet-induced bacterial translocation can be modulated hormonally and the beneficial effects of fiber on diet-induced BT appears to be hormonally mediated.     

活体部分小肠移植一例报告

目的 对临床活体部分小肠移植进行总结。方法 为1例患超短肠综合的18岁男必患者施行父亲供肠的活体部分小肠移植术,移植肠段为150cm长之回肠,以UW液灌洗。移植肠动、静脉分别与受者的腹主动脉及下腔静脉端侧吻合,移植肠近端与受者的空肠近端行端端吻合,远端与受者的空肠远端行侧端吻合,末端造口。术后给予抗排斥、抗感染、抗凝及营养支持等治疗。结果 术后曾出现贫血、单纯疱疹病毒感染和 急性排斥反应,经积极处理行到控制目前患者已健康存活14月余。结论 活体部分小肠移植是治疗短肠综合征的一理想方法。     

Oral glutamine prevents gut mucosal injury and improves mucosal recovery following lipopolysaccharide endotoxemia in a rat

OBJECTIVE: To evaluate the effects of oral glutamine in preventing mucosal damage caused by lipopolysaccharide (LPS) endotoxemia in a rat. METHODS: Male Sprague Dawley rats, weighing 250 to 280 g, were divided into three experimental groups: CONTR rats (Group A), LPS rats (Group B) were treated with lipopolysaccharide given I.P. at dose 10 mg/kg every 24 h (two injections), and LPS-GLN rats (Group C) were treated with oral glutamine given in drinking water (2%) 72 h before and following injection of LPS. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined 24 h after last LPS injection. RESULTS: LPS rats demonstrated a significant decrease in bowel and mucosal weight in jejunum and ileum, mucosal DNA and protein in jejunum and ileum, and villus height and crypt depth in jejunum and ileum compared with sham animals. LPS rats also had a significantly greater Park injury score in jejunum and ileum, a lower cell proliferation index in jejunum and ileum, and higher apoptotic index in jejunum and ileum compared with control rats. LPS-GLN animals showed a significant increase in bowel weight in jejunum, mucosal weight in jejunum and ileum, mucosal DNA in jejunum and ileum, villus height in jejunum and ileum, and cell proliferation index compared with LPS animals. The Park injury score was significantly lower in LPS-GLN rats compared with LPS animals. CONCLUSIONS: Oral glutamine supplementation prevents mucosal injury and improves intestinal recovery after LPS endotoxemia in a rat.     

Nitrergic mechanisms mediating inhibitory control of longitudinal smooth muscle contraction in mouse small intestine

Studies using genetic manipulation to investigate mechanisms of control of physiologic function often necessitate mouse models. However, baseline functional analysis of murine small intestinal motility has not been well defined. Our aim was to define nitrergic mechanisms regulating mouse small intestinal longitudinal muscle. Endogenous nitric oxide (NO) is an important neuroregulatory substance mediating inhibition of contractile activity in murine small bowel. Full-thickness muscle strips of jejunum and ileum from C57BL/6 mice (n ≥6 mice) cut in the direction of longitudinal muscle were studied. Numerous conditions of electrical field stimulation (EFS) and effects of exogenous NO and NO donors were studied in the absence or presence of inhibitors of nitric oxide synthase (NOS) and 1H-[1,2,4]-oxadiazaolo-[4,3-a]-quinoxalin-1-one (ODQ), a downstream inhibitor of guanylyl cyclase. EFS induced a frequencydependent inhibition of contractile activity in both jejunum and ileum (P < 0.05). As the voltage of EFS was increased, inhibition turned to excitation in the jejunum; in contrast, the ileum demonstrated a voltage-dependent increasing inhibition (P < 0.05 each). EFS-induced inhibition was blocked by NOS inhibitors and ODQ. NO donors inhibited spontaneous contractile activity abolished by ODQ. NO appears to be an endogenous inhibitory neurotransmitter in murine longitudinal small bowel muscle. Nitrergic mechanisms mediate inhibitory control of murine longitudinal small intestinal muscle. Differences exist in neuroregulatory control between jejunum and ileum that may be related to their known difference in motor patterns. Presented at the Forty-Fifth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 15–19, 2004 (poster presentation). Parts of this work has been published in abstract form (Gastroenterology 2004; 126(Suppl 2): A784). This work was supported by National Institutes of Health grant R01-DK-39337 (M.G.S.) and by the Mayo Foundation.